KR101008024B1 - Apparatus for fabricating bio-chip - Google Patents

Abstract

A biochip manufacturing apparatus capable of manufacturing a biochip by photolithography without using a mask is disclosed. According to an embodiment of the present invention, a biochip may be manufactured by photolithography using a spatial light modulator without using a mask at all. In addition, according to one embodiment of the invention, an optical system for reacting bases in a closed reaction chamber and exposing the bases is external to the reaction chamber. The distortion of the generated image may be corrected through the deformable mirror. Therefore, the lowering of the yield due to the influence of moisture and ozone can be prevented, and the biochip can be manufactured with high precision.

Description

Apparatus for fabricating bio-chip

Embodiments of the present invention relate to a biochip manufacturing apparatus capable of manufacturing a biochip by photolithography without using a mask.

Biochips, for example, are biopsy devices made of a small chip like a semiconductor chip by combining biological organisms such as enzymes, proteins, antibodies, DNA, microorganisms, animal and animal cells and organs, nerve cells, and the like. In particular, a DNA chip is a DNA detection device in which DNAs of hundreds to hundreds of thousands of different nucleotide sequences whose functions in cells are found on a substrate such as glass or a semiconductor are arranged in a single space instead of a double helix in a small space. Here, a collection of DNAs having the same nucleotide sequence of a single helix is commonly called a spot, and a spot is usually composed of 20 to 30 bases linked together.

When the mRNA of the sample is flowed into the DNA chip, only a gene corresponding to a specific spot, that is, a gene having a sequence complementary to the specific sequence of the specific spot, is bound to the corresponding spot, and a gene not bound to the spots in the DNA chip. They are washed away. Since the function of the nucleotide sequence of the spots arranged on the DNA chip is known, it is easy to know the genetic information of the sample by examining which spots in the DNA chip are bound to the gene. Therefore, the DNA chip can be used to analyze the expression or variation of unique genes expressed in specific cells or tissues relatively quickly. In addition, DNA chips may be used for mass gene expression analysis, pathogenic bacteria infection, antibiotic resistance test, biological response to environmental factors, food safety test, criminal identification, new drug development, animal and plant quarantine, and the like.

Such a biochip is prepared by stacking DNA bases such as A (adenine), G (guanine), C (cytosine), and T (thymine) in different order for each spot in the biochip, for example, 20 to 30 times. Can be. In order to form hundreds of thousands of different spots with exactly the desired base sequence in one biochip, a very precise manufacturing method is required. The most typical biochip manufacturing method is a photolithography process similar to a general semiconductor manufacturing method. According to this method, the remaining area except for the area to be reacted with a specific base in the biochip under manufacture is covered with a mask, and then the biochip is irradiated with light. At this time, all of the bases used in the reaction are coupled to a photolabile material, so that the bases do not bind to each other. However, when light is irradiated, the photodegradable substance bound to the base is decomposed, and thus the base irradiated with light can bind with other bases. Thus, it is possible to bind the desired specific base only to bases that are not covered by the mask and are exposed to light. According to this method, biochips can be manufactured very accurately, but because of the use of expensive photolithography equipment and the use of a large number of masks, which are four times the number of base layers, the production cost of biochips is high and the manufacturing time is long. On the side.

Embodiments of the present invention provide a biochip manufacturing apparatus capable of manufacturing a biochip, such as a DNA chip by a photolithography method without using a mask.

Embodiments of the present invention also provide a biochip manufacturing apparatus capable of monitoring the manufacturing process of the biochip in real time.

Biochip manufacturing apparatus according to an embodiment of the present invention, the biochip is disposed, the reaction chamber for sealing the biochip from the outside; An exposure system including a light source and a spatial light modulator, forming an optical image using the spatial light modulator, and providing the formed optical image to a biochip; And a monitoring system for monitoring in real time an optical image provided to the biochip by the exposure system.

According to an embodiment of the present invention, the spatial light modulator may be, for example, a reflective spatial light modulator made of LCoS or DMD.

In this case, the biochip manufacturing apparatus according to an embodiment of the present invention further includes a light path changing unit for transmitting the light generated from the light source to the spatial light modulator and transmitting the light reflected from the spatial light modulator to the reaction chamber. can do.

The light path changing unit may include, for example, a polarization beam splitter disposed between the light source and the spatial light modulator, a polarizer disposed between the light source and the polarization beam splitter, and a quarter disposed between the polarization beam splitter and the spatial light modulator. It may include a wave plate.

On the other hand, the exposure system, a light diffusing element disposed between the light source and the polarizer, a lens element or mirror element disposed between the quarter wave plate and the spatial light modulator, disposed between the polarizing beam splitter and the reaction chamber It may further include a distortion correction element, and a projection optical system disposed between the distortion correction element and the reaction chamber.

For example, the distortion correction element may be a deformable mirror having a reflective surface deformable by mechanical or electrical manipulation to correct distortion of the optical image.

In addition, according to an embodiment of the present invention, the monitoring system is configured to face one of the light exit surfaces of the polarization beamsplitter to detect an optical image reflected from the biochip in the reaction chamber and transmitted through the polarization beamsplitter. Can be arranged.

According to another embodiment of the present invention, the monitoring system may be disposed at the rear of the reaction chamber along the traveling direction of the light in order to detect the light image transmitted through the reaction chamber and the biochip.

According to embodiments of the present invention, the monitoring system may include an image sensor and an imaging lens or an imaging mirror for imaging an optical image on the image sensor.

The image sensor may have an array of a plurality of fine pixels, and may be any one of a light multiplier (PMT), a charge coupled device (CCD), and a CMOS image sensor (CIS).

On the other hand, according to another embodiment of the present invention, the spatial light modulator, for example, a transmissive spatial light modulator using a non-linear optical medium in which a plurality of patterns are pre-recorded in the form of a three-dimensional array according to a liquid crystal element or a hologram method. Can be.

In this case, the exposure system further comprises a light diffusing element and a lens element or a mirror element arranged along the direction of light propagation between the light source and the spatial light modulator, and the direction of light propagation between the spatial light modulator and the reaction chamber. It may further include a distortion correction element and a projection optical system disposed along.

According to an embodiment of the present disclosure, the biochip manufacturing apparatus may further include a light path changing unit configured to transfer light generated from the light source to a reaction chamber and to transmit light reflected from the biochip in the reaction chamber to a monitoring system. Can be.

The light path changing unit may include, for example, a polarization beam splitter disposed between the light diffusion element and the lens element or a mirror element, a polarizer disposed between the light diffusion element and the polarization beam splitter, and the polarization beam splitter and the lens element. Or a quarter wave plate disposed between the mirror elements.

According to exemplary embodiments of the present invention, since the biochip may be manufactured by photolithography without using a mask at all, manufacturing cost and manufacturing time of the biochip may be reduced. In addition, since the optical system for reacting the bases and exposing the bases in a closed reaction chamber exists outside the reaction chamber, it is possible to prevent a decrease in yield due to influence of moisture and ozone. Furthermore, according to exemplary embodiments of the present invention, the distortion of the optical image due to the reaction chamber can be corrected, and the manufacturing process of the biochip can be monitored in real time, so that the biochip can be manufactured with high precision.

Hereinafter, with reference to the accompanying drawings, the configuration and operation of the biochip manufacturing apparatus according to the embodiments of the present invention will be described in detail.

First, FIG. 1 is a conceptual diagram schematically illustrating the principle of a biochip manufacturing apparatus according to embodiments of the present invention. Referring to FIG. 1, the biochip manufacturing apparatus according to the exemplary embodiments of the present disclosure may roughly form a light source 101 for generating light and a spatial light modulator 108 for forming an image of light to be illuminated on the biochip instead of acting as a mask. ), A distortion correction element 110 for correcting distortion of an optical image, a reaction chamber 120 in which a base reaction for manufacturing a biochip occurs, and an image sensor inspecting an optical image illuminated by the biochip in the reaction chamber 120 ( 113).

The spatial light modulator 108 is composed of an array of a plurality of fine pixels, and can be turned on and off in each pixel unit to selectively transmit or reflect light. The transmissive spatial light modulator selectively transmits or blocks light for each pixel, and the reflective spatial light modulator may selectively reflect or absorb light for each pixel. Thus, by controlling the on / off of each pixel in the spatial light modulator 108, it is possible to create an image of light to be illuminated on the biochip without using a mask. For example, a liquid crystal element can be used as the transmissive spatial light modulator. It is also possible to use Liquid Crystal on Silicon (LCoS) as the reflective spatial light modulator, or to use an array of micromirrors provided by micro-electrical mechanical system (MEMS) technology, such as a digital micromirror device (DMD).

Meanwhile, a nonlinear optical medium in which a plurality of patterns are previously recorded in the form of a three-dimensional array may be used as a spatial light modulator according to the hologram method. The nonlinear optical medium may be formed such that optical images of different patterns are generated while the diffraction conditions of the incident light change according to the incident angle, wavelength, or focusing depth of the incident light. Such a nonlinear optical medium may be obtained, for example, by sequentially irradiating the nonlinear optical medium with different interference patterns. When using a nonlinear optical medium, it is not possible to arbitrarily create an undefined optical image, but the images of the mask to be used in the biochip manufacturing process are stored in the nonlinear optical medium in advance, and the incident angle, wavelength or focusing depth of the incident light is changed. It is possible to extract the required image. Such nonlinear optical media can be regarded as a type of transmissive spatial light modulator.

The reaction chamber 120 is sealed to separate the biochip and the reactant (eg, DNA base to be bound to the biochip) from the outside. In this case, a transparent window 125 (see FIG. 3A) is disposed on an incident surface of the reaction chamber 120 to allow light to enter and exit the reaction chamber 120. However, the transparent window 125 of the reaction chamber 120 is a major cause of distorting the optical image. In addition, the optical image is easily distorted when the light is reflected or transmitted in the spatial light modulator 108, and the optical image may be distorted by various other optical elements. The distortion correction element 110 serves to prevent and correct distortion of an optical image provided to the biochip 130 (see FIG. 3A) in the reaction chamber 120. The distortion correction element 110 may be a mirror provided with aberrations intentionally opposed to the aberrations so as to compensate for various aberrations existing on the optical path from the spatial light modulator 108 to the biochip in the reaction chamber 120. have.

For example, as the distortion correction element 110, a deformable mirror in which the reflecting surface is arbitrarily deformable by mechanical or electrical manipulation may be used. The deformable mirror has a reflective surface made of a flexible member, and below the reflective surface, fine electrical or mechanical devices for locally pushing or pulling the flexible reflective surface are arranged in the form of a two-dimensional array. Thus, it is possible to intentionally provide aberration to the mirror surface of the deformable mirror. For example, providing spherical aberrations to the deformable mirrors as opposed to spherical aberrations accumulated on the optical path from the spatial light modulator 108 to the biochip in the reaction chamber 120 can completely cancel the spherical aberration.

Correction of the distortion may be performed by referring to the optical image reflected from the biochip and detected by the image sensor 113. For example, before starting the reaction of the base, the spatial light modulator 108 creates an image of parallel or vertical parallel lines, a mesh image in the form of a mesh, or a checker board, and provides the biochip to the biochip. . The image of this pattern is reflected from the biochip and detected by the image sensor 113, wherein the mirror surface of the deformable mirror is such that the image detected by the image sensor 113 is exactly the same as the image produced by the spatial light modulator 108. Can be operated.

After the distortion is corrected, the biochip may be manufactured by irradiating light onto the biochip while simultaneously providing a reactant in the reaction chamber 120. In this case, the image sensor 113 continuously monitors the optical image provided to the biochip, so that the non-distorted optical image is provided to the biochip.

2 illustrates in more detail a biochip manufacturing apparatus 100 according to an embodiment of the present invention implemented according to the principles described above. Referring to FIG. 2, the biochip manufacturing apparatus 100 according to an exemplary embodiment may include a light source 101, a light diffusing element 102, and a polarizer in a light propagation direction along a first optical axis OX. (103), polarizing beam splitter 105, quarter wave plate (λ / 4 plate) 106, lens element 107, and spatial light modulator 108 in sequence. In addition, the image sensor 113, the imaging lens 112, the polarization beam splitter 105, the distortion correction element 110, the projection optical system 111, and the reaction chamber 120 are sequentially formed from above along the second optical axis OX ′. ) Is arranged. The polarizing beam splitter 105 is commonly located on the first optical axis OX and the second optical axis OX ′. Here, the light source 101, the light diffusing element 102, the lens element 107, the spatial light modulator 108, the distortion correcting element 110, and the projection optical system 111 are biochips manufactured in the reaction chamber 120. An exposure system for exposing the light is constituted. In addition, the imaging lens 112 and the image sensor 113 constitute a monitoring system for monitoring the manufacturing process of the biochip in real time. The polarizer 103, the polarization beam splitter 105, and the quarter wave plates 104 and 106 constitute an optical path changing unit for converting the optical paths.

Note that although the optical systems used in this embodiment and other embodiments to be described below are described as being refractive optical systems mainly composed of lenses, even if a reflective optical system including a concave mirror or a convex mirror is used instead of the refractive optical system, The same action and effect can be obtained. For example, a mirror element and an imaging mirror may be used in place of the lens element and the imaging lens described below, respectively. In addition, depending on the design, a reflective refractive optical system including both a refractive lens and a reflective mirror may be used. The following description focuses on the refractive optical system for convenience.

According to one embodiment of the invention, the light source 101 of the exposure system emits light for exposure to be illuminated on the biochip to be manufactured. Such exposure light may be coherent light or incoherent light. In order to obtain a high resolution optical image, it is advantageous to use a light source that emits light of a short wavelength (eg, an ultraviolet region), but it is not necessarily limited thereto. The light source 101 may use all conventional light sources used in general photolithography apparatus. A light emitting diode (LED) or a laser diode (LD) emitting monochromatic light may be used, or a lamp having white light or mixed color light may be used. For example, a mercury lamp, a D2 lamp or an Xe lamp can be used as the light source 101.

The exposure light emitted from the light source 101 may pass through the light diffusing element 102. The light diffusing element 102 evenly spreads the light so as to have a uniform intensity through its entire cross section. The exposure light has an overall uniform intensity so that the exposed portion of the biochip to be manufactured is illuminated at the same intensity. This ensures that the base is bound exactly to the desired gene spot on the biochip. Although the light diffusing element 102 is briefly shown in FIG. 2 as one flat plate type element, it is possible to configure the light diffusing element 102 in various forms. For example, the light diffusing element 102 may be a rod-shaped light integrator, a diffraction grating, a micro lens or a diffuser. In addition, the light diffusion device 102 may be configured with a plurality of optical devices to improve uniformity.

2 shows that the light source 101 and the light diffusing element 102 are arranged on the optical axis OX like the other optical elements, but a suitable light transmitting means such as an optical fiber (not shown) may be used. In this case, it may be disposed away from the optical axis OX. When the optical fiber is used, the light diffusing element 102 may be omitted since the light emitted from the light source 101 may be spread evenly while traveling inside the optical fiber. Using an optical fiber can increase the degree of freedom for the layout design of the light source 101 and reduce the effort for alignment of the light source 101 during assembly.

Next to the light diffusing element 102 is a polarizer 103. The polarizer 103 causes the light for exposure to have a specific polarization state. For example, light passing through the polarizer 103 may have an S-polarized state. However, when the light source 101 is configured to emit light in a specific polarization state, for example, when the light source 101 is a laser that emits light in an S-polarization state, the polarizer 103 may not be used. It may be.

Next, a polarizing beam splitter 105 is disposed. The polarizing beam splitter 105 reflects or transmits incident light according to the polarization state of the incident light. For example, polarizing beamsplitter 105 may transmit S-polarized light and reflect P-polarized light. By using the polarization beam splitter 105, the exposure light emitted from the light source 101 is advanced to the spatial light modulator 108, and the light reflected from the spatial light modulator 108 is advanced to the reaction chamber 120. Can be. In this regard, the polarization beam splitter 105 may be regarded as an optical path changing element. As mentioned above, the polarizing beamsplitter 105, together with the polarizer 103 and quarter wave plates 104, 106, constitutes an optical path changing unit, the principle of which will be described in more detail below. In FIG. 2, the exposure light emitted from the light source 101 passes through the polarization beam splitter 105 and proceeds to the spatial light modulator 108, and the light reflected from the spatial light modulator 108 is polarized beam splitter 105. It is shown to be reflected off. However, according to the embodiment, the exposure light emitted from the light source 101 is reflected by the polarization beam splitter 105 and the light reflected by the spatial light modulator 108 is configured to transmit through the polarization beam splitter 105. It may be. In this case, instead of the quarter wave plate 106, the lens element 107, and the spatial light modulator 108, the distortion correction element 110, the projection optical system 111, and the reaction chamber 120 have a first optical axis. Will be arranged on (OX).

Light transmitted through the polarization beam splitter 105 passes through the quarter wave plate 106. The quarter wave plate 106 serves to convert linearly polarized light into circularly polarized light and vice versa. For example, light in the S-polarized state incident on the quarter wave plate 105 may be converted into light in the left circularly polarized state.

Then, the light converted to the circularly polarized state is incident on the spatial light modulator 108 through the lens element 107. In this case, the lens element 107 may use a special lens such as an aspherical lens in order to minimize the effect of aberration. Although only one single lens element 107 is shown in FIG. 2, the lens element 107 may be configured by a lens group having a plurality of lenses, in which case at least one lens in the lens group may be an aspherical lens. . On the other hand, the spatial light modulator 108 used in this embodiment is a reflective spatial light modulator. For example, LCoS or DMD may be used as the spatial light modulator 108. The spatial light modulator 108 reflects a portion of the incident light and absorbs or deflects the remaining portion out of the light path depending on the illumination pattern to be provided to the biochip in the reaction chamber 120. Therefore, the exposure light reflected by the spatial light modulator 108 will have a light image having a predetermined pattern.

The light reflected by the spatial light modulator 108 is reversed in the circular polarization state. For example, the light is changed from the left circularly polarized state to the right circularly polarized state to pass through the quarter wave plate 106 again. At this time, the light is changed to light in, for example, P-polarized light by the quarter wave plate 106. Then, the light in the P-polarized state is reflected by the polarization beam splitter 105 and travels toward the distortion correction element 110. As described above, the distortion correction element 110 serves to prevent and correct distortion of an optical image provided to the biochip in the reaction chamber 120. For example, the distortion correction element 110 may intentionally have aberrations opposite to the aberrations to compensate for the various aberrations present on the optical path from the spatial light modulator 108 to the biochip in the reaction chamber 120. It may be a provided mirror. As the distortion correction element 110, for example, a deformable mirror whose reflection surface can be arbitrarily deformed by mechanical or electrical manipulation can be used.

The light reflected by the distortion correction element 110 is incident to the biochip 130 in the reaction chamber 120 through the projection optical system 111 after passing through the quarter wave plate 104. The projection optical system 111 is for projecting an optical image to a biochip at a high resolution, and may be a lens system composed of a plurality of lenses. The reaction chamber 120 allows the biochip 130 to be manufactured in an enclosed environment. In the light incident surface of the reaction chamber 120, a transparent window 125 is formed to allow light to enter and exit the material remaining after reacting with an inlet 121 (see FIG. 3A) to provide a reacted base. A discharge outlet 122 (see FIG. 3A) is formed. When an optical image having a predetermined pattern formed by the spatial light modulator 108 is provided to the biochip 130, the binding reaction of the base occurs only in the exposed portion of the biochip 130. Therefore, according to one embodiment of the present invention, it is possible to bind a specific base to a desired portion in the biochip 130 without using a mask.

Meanwhile, the monitoring system including the imaging lens 112 and the image sensor 113 may detect the optical image reflected from the biochip 130 in the reaction chamber 120 and transmitted through the polarization beam splitter 105. It faces one of the light exit surfaces of the polarization beam splitter 105. Therefore, the light reflected by the biochip 130 passes through the projection optical system 111 and the quarter wave plate 104 again. At this time, the polarization state of the light is changed from the P-polarized state to the S-polarized state, for example. Then, the light passes through the polarization beam splitter 105 through the distortion correction element 110 and is then imaged onto the image sensor 113 by the imaging lens 112. The image sensor 113 may monitor the optical image provided to the biochip 130 in real time. Therefore, according to one embodiment of the present invention, it is possible to check whether the correct image pattern is provided to the biochip 130 through the image sensor 113. This makes it possible to correct errors in real time through a feedback process between the image sensor 113 and the spatial light modulator 108. The image sensor 113 may be formed of, for example, an array of hundreds of thousands to hundreds of millions of fine pixels. For example, a photomultiplier tube (PMT), a charge coupled device (CCD), a CMOS image sensor (CIS), or the like may be used as the image sensor 113.

3A to 3E exemplarily illustrate a process in which a biochip is manufactured using the biochip manufacturing apparatus 100 described above. Referring to FIG. 3A, a biochip 130 being manufactured is disposed in the reaction chamber 120. The upper part of the reaction chamber 120 is formed with a transparent window 125 through which exposure light can be incident, and an outlet 122 for reacting with the inlet 121 for providing a base to be reacted and for discharging the remaining base. It is formed on the side of the reaction chamber 120. 3A schematically shows only four gene spots 126 arranged on the biochip 130. A photolabile material 127 is bound to the base of each gene spot 126.

At this time, as shown in FIG. 3B, illuminating only the second and fourth spots through an exposure system including a spatial light modulator 108 removes the photodegradable material 127 bound to the base. At the same time, when the base is provided in the reaction chamber 120 through the inlet 121, the newly introduced base is bound only to the base from which the photodegradable material 127 is removed. Then, as shown in Figure 3c, the guanine (G) layer is newly stacked in the second and fourth gene spot. It can be seen that the photodegradable material 127 is also bound to the newly bonded guanine base.

Thereafter, as shown in FIG. 3D, light is provided to the first and second gene spots through an exposure system while providing cytosine C in the reaction chamber 120 through the inlet 121. Then, the photodegradable material 127 is removed only at the first and second gene spots, and thus, as shown in FIG. 3E, cytosine (C) is stacked only at the first and second gene spots. By exposing the biochip 130 in a predetermined image pattern in this manner and then providing specific bases in the reaction chamber 120, it is possible to bind specific bases to desired gene spots in the biochip 130. By repeating this process, the desired base sequence can be generated.

According to the embodiment of the present invention described above, since the spatial light modulator 108 is used, the biochip may be manufactured by photolithography without using a mask at all. Thus, the design, manufacture, inspection and placement of the mask can be omitted, thereby reducing the manufacturing cost and manufacturing time of the biochip. In addition, since the optical system for exposing the base and reacting the biochip in the closed reaction chamber 120 exists outside the reaction chamber 120, the yield of the biochip due to the influence of moisture and ozone, etc., is prevented. can do. In addition, the distortion correction element 110 such as the deformable mirror described above may be used to correct distortion of the optical image generated in the optical path between the spatial light modulator 108 and the reaction chamber, and the image sensor 113 may be adjusted. It can be used to monitor the manufacturing process of the biochip in real time, it is possible to manufacture the biochip with high precision.

4 schematically illustrates a biochip manufacturing apparatus 200 according to another embodiment of the present invention. As compared with the biochip manufacturing apparatus 100 illustrated in FIG. 2, the biochip manufacturing apparatus 200 illustrated in FIG. 4 includes the reaction chamber 120 in which the imaging lens 112 and the image sensor 113 are arranged along the advancing direction of light. The difference is that they are placed behind them. The rest of the configuration and operation of the biochip manufacturing apparatus 200 according to the embodiment of FIG. 4 is the same as the biochip manufacturing apparatus 100 of FIG. 2. However, the quarter wave plate 104 of FIG. 2 need not be disposed in the optical path between the distortion correction element 110 and the reaction chamber 120. In this embodiment, in order for the imaging lens 112 and the image sensor 113 to be disposed behind the reaction chamber 120, a transparent window needs to be disposed on both the front side and the rear side of the reaction chamber 120. In addition, the substrate of the biochip 130 manufactured in the reaction chamber 120 is also made of a transparent material. Then, the optical image irradiated through the front surface of the reaction chamber 120 to irradiate the biochip 120 passes through the substrate of the biochip 130 and the rear surface of the reaction chamber 120, and through the imaging lens 112, the image sensor 113. Can be phased up. 4, the imaging lens 112 may be omitted, and the image sensor 113 may be directly attached to the rear surface of the reaction chamber 120.

5 schematically shows a biochip manufacturing apparatus 300 according to another embodiment of the present invention. 5 differs from the embodiment shown in FIG. 2 in that it uses a transmissive spatial light modulator rather than a reflective spatial light modulator as the spatial light modulator 108 '. Thus, as the spatial light modulator 108 ′, for example, a liquid crystal element may be used, or a nonlinear optical medium in which a plurality of patterns are pre-recorded in the form of a three-dimensional array in a hologram manner. According to the present embodiment, since the transmissive spatial light modulator 108 'is used, the light source 101, the light diffusing element 102, the polarizer 103, the polarization beam splitter 105, and the quarter wave plate 106 are used. ), A common optical axis in which the lens element 107, the spatial light modulator 108 ′, the distortion correction element 110, the projection optical system 111, and the reaction chamber 120 are bent by the distortion correction element 110. (OX) can be arranged in sequence. According to the present exemplary embodiment, the light path changing unit including the polarizer 103, the polarization beam splitter 105, and the quarter wave plate 106 transmits light generated from the light source 101 to the reaction chamber 120. And light reflected from the reaction chamber 120 to the monitoring system (ie, imaging lens 112 and image sensor 113).

In the biochip manufacturing apparatus 300 illustrated in FIG. 5, the light emitted from the light source 101 passes through the spatial light modulator 108 ′ and has a light image. The light transmitted through the spatial light modulator 108 'is reflected by the distortion correction element 110 disposed thereafter, and then see the biochip 130 in the reaction chamber 120 through the projection optical system 111 (see FIG. 3A). Can be projected to). Meanwhile, the light reflected from the biochip 130 proceeds through the opposite path. That is, the light from the biochip 130 passes through the quarter wave plate 106 through the projection optical system 111, the distortion correction element 110, the spatial light modulator 108 ′, and the lens element 107. . At this time, since the polarization state of the light is changed by the quarter wave plate 106, the reflected light from the biochip 130 is reflected by the polarization beam splitter 105 and is image sensor 113 through the imaging lens 112. Can be phased up.

6 schematically shows a biochip manufacturing apparatus 400 according to another embodiment of the present invention. In the biochip manufacturing apparatus 400 illustrated in FIG. 6, the imaging lens 112 and the image sensor 113 are disposed behind the reaction chamber 120 when compared with the biochip manufacturing apparatus 300 illustrated in FIG. 5. The biggest difference is In addition, in the present embodiment, since the light starting from the light source 101 does not need to be returned to the original path or branched to another path while reaching the image sensor 113 via the biochip 130, the light path is changed. Does not require units Thus, the polarizer 103, the polarization beam splitter 105, and the quarter wave plate 106, which have been used in the above embodiments, need not be used in this embodiment.

In the case of the present embodiment shown in FIG. 6, similarly to the embodiment of FIG. 5, a transmissive spatial light modulator other than the reflective spatial light modulator is used as the spatial light modulator 108 '. Thus, as the spatial light modulator 108 ′, for example, a liquid crystal element may be used, or a nonlinear optical medium in which a plurality of patterns are previously recorded in the form of a three-dimensional array in a hologram manner. Therefore, the operation of the biochip manufacturing apparatus 400 according to the present embodiment may be applied in the same manner as described with reference to FIG. 5.

Meanwhile, in the present exemplary embodiment, the imaging lens 112 and the image sensor 113 are disposed behind the reaction chamber 120 as in the exemplary embodiment of FIG. 4. For this arrangement, a transparent window needs to be disposed on both the front side and the rear side of the reaction chamber 120. In addition, the substrate of the biochip 130 manufactured in the reaction chamber 120 is also made of a transparent material. Then, the optical image irradiated through the front surface of the reaction chamber 120 to irradiate the biochip 120 passes through the substrate of the biochip 130 and the rear surface of the reaction chamber 120, and through the imaging lens 112, the image sensor 113. Can be phased up. In addition, as described above with reference to FIG. 4, in the embodiment of FIG. 6, the imaging lens 112 may be omitted and the image sensor 113 may be directly attached to the rear surface of the reaction chamber 120.

So far, various embodiments have been described and illustrated in the accompanying drawings to aid the understanding of the present invention. However, it should be understood that these embodiments are merely illustrative of the invention and do not limit it. And it is to be understood that the invention is not limited to the details shown and described. For example, although the above-described embodiments have been described as using a refractive optical system mainly composed of lenses, the same operation and effect can be obtained even when using a reflective optical system including a concave mirror or a convex mirror. This is because various other modifications may occur to those skilled in the art.

1 is a conceptual diagram schematically illustrating the principle of a biochip manufacturing apparatus according to embodiments of the present invention.

FIG. 2 illustrates a biochip manufacturing apparatus according to an embodiment of the present invention, which implements the principle illustrated in FIG. 1 in more detail.

3A to 3E exemplarily illustrate a process of manufacturing a biochip in a biochip manufacturing apparatus according to an embodiment of the present invention shown in FIG. 2.

Figure 4 schematically shows a biochip manufacturing apparatus according to another embodiment of the present invention.

5 schematically shows a biochip manufacturing apparatus according to another embodiment of the present invention.

6 schematically shows a biochip manufacturing apparatus according to another embodiment of the present invention.

<Description of Symbols for Main Parts of Drawings>

100,200,300,400 ..... Biochip Manufacturing Equipment

101 ..... light source 102 ..... light diffusing element

103 ..... polarizer 105 ..... polarized beam splitter

106 ..... 1/4 wave plate 107 ..... lens element

108 ..... Spatial Light Modulator 110 ..... Distortion Compensation Element

113 ..... Image sensor 120 ..... Reaction chamber

Claims (21)

A reaction chamber in which the biochip is disposed and seals the biochip from the outside; An exposure system including a light source and a spatial light modulator, forming an optical image using the spatial light modulator, and providing the formed optical image to a biochip; And And a monitoring system for monitoring in real time an optical image provided to the biochip by the exposure system. The method of claim 1, The spatial light modulator is a biochip manufacturing apparatus is a reflective spatial light modulator. The method of claim 2, The spatial light modulator is a biochip manufacturing apparatus consisting of a liquid crystal on silicon (LCoS) or a digital micromirror device (DMD). The method of claim 2, And a light path changing unit which transmits the light generated by the light source to the spatial light modulator and transmits the light reflected by the spatial light modulator to the reaction chamber. The method of claim 4, wherein The optical path changing unit includes a polarization beam splitter disposed between the light source and the spatial light modulator, a polarizer disposed between the light source and the polarization beam splitter, and a quarter wave plate disposed between the polarization beam splitter and the spatial light modulator. Biochip manufacturing apparatus comprising a. The method of claim 5, The exposure system includes a light diffusion element disposed between the light source and the polarizer, a lens element or mirror element disposed between the quarter wave plate and the spatial light modulator, and a distortion correction disposed between the polarization beam splitter and the reaction chamber. And a projection optical system disposed between the distortion correction element and the reaction chamber. The method of claim 6, And the distortion correction element is a deformable mirror having a reflective surface deformable by mechanical or electrical manipulation to correct distortion of the optical image. The method of claim 5, And said monitoring system is opposed to one of the light exit surfaces of said polarizing beamsplitter in order to detect an optical image reflected from the biochip in the reaction chamber and transmitted through said polarization beamsplitter. The method of claim 5, The monitoring system is a biochip manufacturing apparatus disposed behind the reaction chamber along the direction of the light to detect the light image transmitted through the reaction chamber and the biochip. 10. The method according to claim 8 or 9, The monitoring system is a biochip manufacturing apparatus having an image sensor and an imaging lens or an imaging mirror to form an optical image on the image sensor. The method of claim 10, The image sensor includes an array of a plurality of fine pixels, and is one of a photomultiplier tube (PMT), a charge coupled device (CCD), and a CMOS image sensor (CIS). The method of claim 1, The spatial light modulator is a biochip manufacturing apparatus is a transmissive spatial light modulator. 13. The method of claim 12, The spatial light modulator is a biochip manufacturing apparatus using a nonlinear optical medium in which a plurality of patterns are previously recorded in the form of a three-dimensional array according to a liquid crystal device or a hologram method. 13. The method of claim 12, The exposure system further includes a light diffusing element and a lens element or a mirror element which are sequentially arranged along the traveling direction of light between the light source and the spatial light modulator, and further along the traveling direction of light between the spatial light modulator and the reaction chamber. Biochip manufacturing apparatus further comprising a distortion correction element and a projection optical system arranged in sequence. The method of claim 14, And the distortion correction element is a deformable mirror having a reflective surface deformable by mechanical or electrical manipulation to correct distortion of the optical image. The method of claim 14, And a light path changing unit for transferring the light generated from the light source to the reaction chamber and transferring the light reflected from the biochip in the reaction chamber to a monitoring system. The method of claim 16, The optical path changing unit includes a polarization beam splitter disposed between the light diffusion element and the lens element or mirror element, a polarizer disposed between the light diffusion element and the polarization beam splitter, and the polarization beam splitter and the lens element or mirror. Biochip manufacturing apparatus comprising a quarter wave plate disposed between the elements. The method of claim 17, And said monitoring system is opposed to one of the light exit surfaces of said polarizing beamsplitter in order to detect an optical image reflected from the biochip in the reaction chamber and transmitted through said polarization beamsplitter. The method of claim 14, The monitoring system is a biochip manufacturing apparatus disposed behind the reaction chamber along the direction of the light to detect the light image transmitted through the reaction chamber and the biochip. 20. The method according to claim 18 or 19, The monitoring system is a biochip manufacturing apparatus having an image sensor and an imaging lens or an imaging mirror to form an optical image on the image sensor. The method of claim 20, The image sensor includes an array of a plurality of fine pixels, and is one of a photomultiplier tube (PMT), a charge coupled device (CCD), and a CMOS image sensor (CIS).

Images