KR102690597B1 - Microlens array based ultrathin microscope - Google Patents

Abstract

The present invention relates to an ultra-thin microscope based on a microlens array, wherein the microscope includes a filter unit that selectively transmits fluorescence expressed in a measurement sample; and an imaging unit that acquires an image from the light transmitted from the filter unit. It includes, wherein the filter part is formed in contact with or spaced apart from one side of the transparent substrate, and the imaging part is a microlens array formed on the opposite side of the transparent substrate on which the filter part is formed and collects image information of the microlens array. It relates to a microlens array-based ultra-thin microscope that includes an image sensor.

Description

Microlens array-based ultra-thin microscope {MICROLENS ARRAY BASED ULTRATHIN MICROSCOPE}

The present invention relates to an ultra-thin microscope based on a microlens array.

In addition to the recent coronavirus outbreak, the world is currently being infected with various viruses, so the demand for on-site diagnostic devices for viruses is increasing, and reflecting this, the market is also steadily increasing.

For example, it is used to detect specific target substances in liquid samples such as blood samples in disease diagnosis, etc., or to examine trace amounts of biological substances in various fields such as biology, environment, and chemistry, and a microscope is applied to read fluorescence signals. It is becoming. Existing microscopes are based on photodiodes, allowing for accurate inspection, but they cannot observe complex structures, and have the disadvantage of requiring replacement of fluorescence filters in case of multiple fluorescence. In addition, the microscopes currently being developed have the disadvantage of being expensive and bulky, and it is difficult to acquire images or high-resolution images.

Accordingly, the present invention can design an inexpensive, ultra-thin microscope using a camera and filter manufactured using a semiconductor process, and the imaging of the ultra-thin microscope according to the present invention can be used not only for on-site diagnostic devices but also for various fields. You can utilize it.

In order to solve the above-mentioned problems, the present invention uses a microlens array and filter that can be manufactured in a large-area process and can be easily applied to various substrates, has high versatility, and provides multi-imaging and high-resolution by microlens array. The goal is to provide a microlens array-based ultra-thin microscope that enables on-site diagnosis and/or multiple diagnosis through imaging.

However, the problems to be solved by the present invention are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

According to one embodiment of the present invention, an ultra-thin microscope based on a microlens array, the microscope includes: a filter unit that selectively transmits fluorescence expressed in a measurement sample; and an imaging unit that acquires an image from the light transmitted from the filter unit. It includes, wherein the filter part is formed in contact with or spaced apart from one side of the transparent substrate, and the imaging part is a microlens array formed on the opposite side of the transparent substrate on which the filter part is formed and collects image information of the microlens array. It relates to a microlens array-based ultra-thin microscope that includes an image sensor.

According to one embodiment of the present invention, the microlens array may include a plurality of lenses arranged at pitch intervals of 500 μm to 2 mm, and the diameter of the microlenses may be 2 mm or less.

According to one embodiment of the present invention, the plurality of lenses of the microlens array each provide individual image information, and the image sensor collects the plurality of individual image information of the microlens array to produce a multispectral image. It may be creating.

According to an embodiment of the present invention, the multi-spectral image may include image information of the same position in the measurement sample.

According to an embodiment of the present invention, the image sensor may generate a high-resolution fluorescence image using the multi-spectral image.

According to an embodiment of the present invention, the high-resolution fluorescence image may be separated according to the light wavelength, and a single or multiple detection targets may be analyzed by analyzing the separated high-resolution fluorescence image.

According to one embodiment of the present invention, the image sensor may be formed on an upper part of the microlens array, and the separation distance between the image sensor and the microlens array may be 5 mm or less.

According to an embodiment of the present invention, the distance between the image sensor and the filter unit may be 5 mm or less, and the distance between the measurement sample and the filter unit may be 5 mm or less.

According to one embodiment of the present invention, the thickness of the transparent substrate may be 5 mm or less.

According to an embodiment of the present invention, the transparent substrate may include at least one of glass, transparent polymer, and transparent oxide.

According to one embodiment of the present invention, the filter unit may include a single or a plurality of band-pass filters, and the band-pass filter may transmit fluorescence expressed in the measurement sample and block light from the lighting unit.

According to an embodiment of the present invention, the bandpass filter may include a color filter, a plasmonic filter, or both.

According to one embodiment of the present invention, the transparent substrate includes: a transparent base substrate; and a transparent layer formed on the transparent base substrate; It may include a microlens array formed on the transparent layer, and the transparent layer may include a transparent oxide.

According to one embodiment of the present invention, a first layer formed between the transparent base substrate and the transparent layer; and a second layer formed on the transparent layer corresponding to the position of the first layer, and the first layer and the second layer may each include a light absorption film, a blocking film, or both.

According to an embodiment of the present invention, the first layer is inserted into the transparent layer, and the first layer and the second layer may be single or multiple layers, respectively.

According to an embodiment of the present invention, the microlens array-based ultra-thin microscope may be used to monitor a measurement sample within a microfluidic system.

According to an embodiment of the present invention, the microlens array-based ultra-thin microscope is for on-site diagnosis and may be used to diagnose two or more types of diseases.

According to an embodiment of the present invention, the microlens array-based ultra-thin microscope may further include an illumination unit that irradiates light to the measurement sample.

The present invention can provide a microlens array-based ultra-thin microscope that is capable of generating high-resolution images and can be universally applied to various diagnostic devices by enabling large area, miniaturization, and/or weight reduction compared to existing microscopes.

The present invention enables high-resolution, multiple fluorescence imaging through images acquired from each lens in a microlens array, and can be used for diagnosis, analysis, and/or detection devices in various fields such as bio, chemistry, and environmental fields. , In particular, a fluorescence diagnostic device using fluorescence images can be provided.

Figure 1 exemplarily shows the configuration and operating principle of an ultra-thin microscope based on a microlens array according to an embodiment of the present invention.
Figure 2 is a configuration (a) of a microfluidic system analysis device equipped with an ultra-thin microscope based on a microlens array according to the present invention and a fluorescence image acquired with an ultra-thin microscope based on a microlens array according to an embodiment of the present invention. (b) is shown as an example.
Figure 3 exemplarily shows an optical design for ensuring image continuity in an ultra-thin microscope based on a microlens array according to an embodiment of the present invention.
Figure 4a exemplarily shows a manufacturing process of a microlens array according to the present invention, according to an embodiment of the present invention.
Figure 4b shows an image of a microlens array according to the present invention manufactured by the method of Figure 4, according to an embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. In describing the present invention, if a detailed description of a related known function or configuration is judged to unnecessarily obscure the gist of the present invention, the detailed description will be omitted. Additionally, the terms used in this specification are terms used to appropriately express preferred embodiments of the present invention, and may vary depending on the intention of the user, operator, or customs in the field to which the present invention belongs. Therefore, definitions of these terms should be made based on the content throughout this specification. The same reference numerals in each drawing indicate the same members.

Throughout the specification, when a member is said to be located “on” another member, this includes not only cases where a member is in contact with another member, but also cases where another member exists between the two members.

Throughout the specification, when a part “includes” a certain component, this does not mean excluding other components, but may further include other components.

Hereinafter, the microlens array-based ultra-thin microscope of the present invention, its manufacturing method, and its utilization will be described in detail with reference to examples and drawings. However, the present invention is not limited to these examples and drawings.

The present invention relates to an ultra-thin microscope based on a microlens array. According to one embodiment of the present invention, the ultra-thin microscope based on a microlens array applies an ultra-thin imaging device to obtain light from a measurement sample, for example, fluorescence information. By collecting and imaging fluorescence, this imaging process can be utilized for monitoring, detection, analysis, and/or diagnosis.

According to an embodiment of the present invention, referring to FIG. 1, FIG. 1 exemplarily shows the main configuration of an ultra-thin microscope based on a microlens array according to the present invention, according to an embodiment of the present invention. The microlens array The ultra-thin based microscope includes a filter unit (100); and an imaging unit 200; and may include a transparent substrate 300 between the filter unit 100 and the imaging unit 200. A compact and ultra-thin microscope can be provided through a unique design of the components of the filter unit 100 and the imaging unit 200 and their arrangement relationships, and the versatility of the microscope can be improved.

According to an embodiment of the present invention, the filter unit 100 selectively transmits and controls fluorescence expressed in a measurement sample, and the filter unit 100 may include a single or multiple bandpass filters. .

As an example of the present invention, the band-pass filter may transmit fluorescence expressed in the measurement sample and block light from the lighting unit. Additionally, the fluorescence can be classified and transmitted according to the light wavelength to provide continuous multiple images according to the light wavelength. The bandpass filter may include a color filter, a plasmonic filter, or both.

As an example of the present invention, the filter unit 100 may be formed in contact with one surface of the transparent substrate 300 or may be formed spaced apart. A microlens array 210 is formed on the opposite side (corresponding to the transparent layer 320) of the transparent substrate 300 (corresponding to the transparent base substrate 310 hereinafter) on which the filter unit 100 is disposed, and the transparent substrate 300 ) is used as a lens substrate for the microlens array 210. That is, in the present invention, the filter unit 100 and the imaging unit 200 are combined on the same transparent substrate 300 or the transparent substrate 300 with the microlens array 210 of the imaging unit 200 formed between them. By applying the arranged structure, the size and thickness of the microscope can be reduced and an ultra-thin microscope can be manufactured while enabling high-resolution image acquisition.

According to an embodiment of the present invention, the imaging unit 200 acquires an image from the light transmitted through the filter unit 100, and the imaging unit 200 includes a microlens array 210 and a microlens array ( It may include an image sensor 220 that collects image information 210).

As an example of the present invention, the microlens array 210 has a size of 500 μm to 2 mm; 500 μm to 1 mm; 600 μm to 900 μm; Alternatively, it may include a plurality of lenses arranged at pitch intervals of 700 μm to 800 μm, and as shown in FIG. 3, it may be designed to acquire high-resolution fluorescence images by controlling the overlap area and focal length of fluorescence according to the pitch interval of the microlens. You can. Additionally, the diameter of the microlens is 2 mm or less; 1.5 mm or less; 1 mm or less; 1 μm to 2 mm; 50 μm to 2 mm; 100 μm to 1 mm; It may be 100 μm to 500 μm, and if it is within the above range, it may be advantageous for acquiring high-resolution images. For example, as shown in FIG. 4B, the microlens array may be formed to have a diameter of about 120 μm (or a height of about 20 μm).

As an example of the present invention, the plurality of lenses of the microlens array 210 can each provide individual images as micro cameras and use them to acquire multispectral images. That is, the image sensor can collect a plurality of individual image information of the microlens array 210 to generate a multi-spectral image. As shown in Figure 2, a multi-spectral image is obtained from a fluorescence image expressed in a microfluidic sample in a diagnostic device. In Figure 2 (b), the multi-spectral image is obtained by transmitting the fluorescence expressed in the measurement sample to the light wavelength through the filter unit. It may include multi-spectral images classified and controlled according to. This confirms fluorescence expression in the same space from individual image information (individual images) at the same location in the measurement sample, and the image sensor generates high-resolution fluorescence images using these multi-spectral images, and performs multiple analyzes such as multiple diagnosis. It may be possible.

As an example of the present invention, the high-resolution fluorescence images are classified according to light wavelength, and the separated high-resolution fluorescence images can be analyzed to monitor, analyze, detect, and/or diagnose a single or multiple detection targets.

As an example of the present invention, the image sensor 220 is formed on the top of the microlens array 210, and the image sensor 220 corresponds to a semiconductor sensor, and can be any semiconductor sensor applicable to the technical field of the present invention without limitation. It may be applied and is not specifically mentioned in this specification. For example, the semiconductor sensor may include a CMOS layer and may configure a CMOS ISA setup, etc.

As an example of the present invention, the separation distance between the image sensor 220 and the microlens array 210 is 300 μm to 5 mm; 500 μm to 4 mm; 600 μm to 3 mm; 800 μm to 2 mm; or 800 μm to 1 mm.

According to one embodiment of the present invention, the transparent substrate 300 includes: a transparent base substrate 310; and a transparent layer 320 formed on the transparent base substrate 310, and a microlens array 210 may be formed on the transparent layer 320.

As an example of the present invention, the thickness of the transparent substrate 300 is 300 μm to 1 mm; 500 μm to 1 mm; 600 μm to 900 μm; Alternatively, it is 700 μm to 900 μm, and by applying the above thickness range, it is possible to provide an ultra-thin microscope that can acquire high-resolution fluorescence images.

As an example of the present invention, the transparent substrate 300 is applied without limitation as long as it is a transparent material, and may include, for example, at least one of glass, transparent polymer, and transparent oxide. Transparent layer 320 includes transparent oxide and has a thickness of tens to hundreds of nanometers, for example, 10 nm or more; 20 nm or more; 10 nm to 1000 nm (or less); 10 nm to 500 nm; 30 nm to 300 nm; 50 nm to 200 nm; Or it may be 50 nm to 100 nm.

According to one embodiment of the present invention, in the transparent substrate 300, a region that absorbs and/or blocks light is formed between the microlenses in order to increase the resolution of the fluorescence image, which is formed on the surface of the transparent substrate 300. , may be formed inside or both. For example, a first layer 330a formed between the transparent base substrate 310 and the transparent layer 320 and a second layer 330b formed on the transparent layer 320 corresponding to the position of the first layer 330a. It can be included. Additionally, the first layer 330a may be inserted into the transparent layer 320.

As an example of the present invention, the first layer 330a and the second layer 330b may be the same or different in at least one of thickness, component, diameter, width (or width), and shape. For example, the first layer 330a and the second layer 330b each have a thickness of one hundred nanometers to several tens of micrometers, for example, 100 nm or more; 200 nm or more; 300 nm to 100 μm (or less); 300 nm to 90 μm; 400 nm to 50 μm; or 500 nm to 20 μm.

As an example of the present invention, the first layer 330a and the second layer 330b may each include a light absorption film, a blocking film, or both. The first layer 330a and the second layer 330b are each single or multiple layers, and each layer of the multiple layers may include the same or different films. For example, the first layer 330a and the second layer 330b may be arranged so that different films face each other or may be formed of the same film. Additionally, when the light blocking film and the light absorbing film are formed simultaneously on each of the first layer 330a and the second layer 330b, they may be stacked in layers.

According to one embodiment of the present invention, the gap between the filter unit 100 and the image sensor 220 of the imaging unit 200 is 5 mm or less; And, the distance between the measurement sample S and the filter unit 100 is 5 mm or less, for example, 500 μm to 5 mm; 600 μm to 4 mm; 800 μm to 3 mm; or 800 μm to 2 mm.

According to one embodiment of the present invention, the microscope further includes an illumination unit 400, and the illumination unit 400 is a light emitting element for expressing and/or enhancing a specific wavelength region for imaging by irradiating light to the measurement sample. Includes, for example, a lamp, LED, laser, etc. for irradiating light for fluorescence expression to the measurement sample, but is not limited thereto. The lighting unit 400 can be placed without limitation as long as the fluorescence of the measurement sample can be expressed, and the measurement sample can be placed between the lighting unit 400 and the filter unit 100. For example, as shown in FIG. 2, the lighting unit 400 may be arranged to enable light irradiation to the lower area of the measurement sample in the point-of-care diagnostic chamber.

According to one embodiment of the present invention, the microscope according to the present invention can be used in bio, environmental, and chemical fields as a fluorescence reader, fluorescence diagnostic device, and sensor. For example, in the field of microfluidics, it can be placed on the back of a microfluidic chip to analyze, identify, detect, monitor, analyze, and/or image changes in fluids and analyte targets, such as molecules, particles, and DNA. In addition, it can be applied to an on-site tester to check for various disease infections on site. In addition, it is possible to image the analysis target, providing a new molecular diagnostic device for on-site diagnosis. For example, referring to (a) of FIG. 2, the microfluid analysis device includes a substrate containing a microfluid; a lighting unit formed in a lower region of the substrate; a filter unit at a height spaced apart in a vertical direction from the microfluidic unit to correspond to the position of the lighting unit; A microscope according to the present invention may be configured in which the imaging unit and the imaging unit are arranged in that order. Additionally, the microfluid may include a sensing area.

According to one embodiment of the present invention, the microscope according to the present invention can acquire multi-spectral images and analyze a single or multiple sensing objects. For example, the microscope is a point-of-care diagnostic device for diagnosing two or more types of diseases. It can be used in devices.

According to one embodiment of the present invention, a method for imaging an analysis object using a microscope according to the present invention can be provided, and the imaging can be used to identify, detect, monitor, and/or analyze the analysis object. According to one embodiment of the present invention, the imaging method includes preparing a measurement sample; irradiating light to the measurement sample to produce fluorescence; transmitting the expressed fluorescence through a filter unit to a microlens array; and collecting images from the microlens array. In the step of collecting the image, a multi-spectral image can be generated using individual images acquired from each lens of the microlens array by an image sensor, and the multi-spectral image can be converted into a high-resolution fluorescence image. The multi-spectral image generates multiple images for each wavelength of fluorescence expressed at the same location within the measurement sample, and can be converted into a high-resolution fluorescence image for each wavelength using the multiple images.

The present invention relates to a method for manufacturing a microscope according to the present invention. According to an embodiment of the present invention, the manufacturing method includes preparing a filter unit (S100); Preparing a microlens array (S200); Preparing an image sensor (S300); and a step (S400) of assembling the filter unit, the microlens array, and the image sensor. The microscope formed by the above manufacturing method is as mentioned in the description of the microscope according to the present invention, and the components and composition in each process are not specifically mentioned.

In the manufacturing method of the present invention, the filter unit and the microlens array are formed on a single transparent substrate, as mentioned above, and the microlens array and filter unit can be manufactured in a large area using various transparent substrates through a semiconductor process. It can be used in a variety of devices. In addition, the present invention forms an ultra-thin microscope capable of acquiring high-resolution fluorescence images by forming a filter unit and a microlens array on a single transparent substrate.

As an example of the present invention, the manufacturing order of the filter unit and the microlens array is not particularly limited, but as shown in FIG. 4A, the prepared filter unit can be combined or assembled after manufacturing the microlens array. More specifically, referring to FIG. 4A, patterning a mask PR on a transparent base substrate 310 (S210); Depositing a first metal layer 330a on one surface of the transparent base substrate 310 on which the patterned mask PR is formed (S220); Lifting off the mask PR to form a patterned first metal layer 330a (S230); Depositing a transparent layer 320 to cover the patterned first metal layer 330a (S240); Depositing a patterned second metal layer 330b on top of the transparent layer 320 corresponding to the position of the patterned first metal layer 330a (S250); Forming a patterned transparent polymer layer 210' on the transparent layer 320 exposed by the patterned second metal layer 330b (S260); and forming the microlens array 210 by applying heat to the transparent polymer layer 210' and reflowing it (S270).

As an example of the present invention, the transparent base substrate 310 can be applied without limitation as long as it is a transparent material with a light-transmitting function, such as glass or transparent polymer.

As an example of the present invention, the mask PR may include photoresist such as AZ5214, PR2035, DNR, GXR, AZ5206, PR9260, SU-8, etc.

As an example of the present invention, the first metal layer 330a and the second metal layer 330b may be the same or different in at least one of thickness, composition, diameter, and shape. Preferably, the first metal layer 330a and the second metal layer 330b are patterned in the same shape to have a space in which a microlens array can be formed, for example, the transparent layer 320 in a dot (or circular) shape. ) may be patterned to be exposed. The first metal layer 330a and the second metal layer 330b form a region that can absorb or block light, and may each include a light-blocking metal film such as black polymer, aluminum, or chromium. The first metal layer 330a and the second metal layer 330b may each include a light absorption film, a light blocking film, or both.

As an example of the present invention, the transparent polymer layer 210' can be applied without limitation as long as it is applicable as a microlens material, for example, AZ5214, PR2035, DNR, GXR, AZ5206, PR9260, SU-8, etc., Preferably it may be DNR.

As an example of the present invention, after the step of forming the microlens array (S270), the filter unit 100 may be attached to the opposite side of the transparent base substrate 310 on which the microlens array 210 is formed.

As an example of the present invention, the deposition may be performed using magnetron sputtering, thermal evaporation, chemical vapor deposition (CVD), or plasma enhanced chemical vapor deposition (PECVD). , Atomic layer deposition (ALD), etc. may be used, but are not limited thereto.

As an example of the present invention, the assembling step (S400) involves assembling the lighting unit 400, the filter unit 100, and the imaging unit 200 according to the device on which the microscope is mounted, thereby forming the configuration of the above-mentioned microscope. It can be assembled appropriately, and can be assembled so that the measurement sample is positioned between the lighting unit 400 and the filter unit 100.

As described above, although the embodiments have been described with limited examples and drawings, various modifications and variations can be made by those skilled in the art from the above description. For example, even if the described techniques are performed in a different order than the described method, and/or the described components are combined or combined in a different form than the described method, or are replaced or substituted by other components or equivalents. Adequate results can be achieved. Therefore, other implementations, other embodiments, and equivalents of the claims also fall within the scope of the claims described below.

Claims (18)

As a microlens array-based ultra-thin microscope,
The microscope is,
A filter unit that selectively transmits fluorescence expressed in the measurement sample; and
an imaging unit that acquires an image from the light transmitted from the filter unit;
Including,
The filter unit is formed in contact with or spaced apart from one surface of the transparent substrate,
The imaging unit includes a microlens array formed on an opposite side of the transparent substrate on which the filter unit is formed, and an image sensor that collects image information of the microlens array,
The microlens array includes a plurality of lenses,
Each of the plurality of lenses of the microlens array provides individual image information,
The image sensor generates a multi-spectral image by collecting a plurality of individual image information of the microlens array,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The microlens array includes a plurality of lenses arranged at pitch intervals of 500 μm to 2 mm,
The diameter of the microlens is 2 mm or less,
Ultra-thin microscope based on microlens array.
delete According to paragraph 1,
The multi-spectral image includes image information of the same position in the measurement sample,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The image sensor generates a high-resolution fluorescence image using the multi-spectral image,
Ultra-thin microscope based on microlens array.
According to clause 5,
The high-resolution fluorescence image is separated according to the light wavelength,
Analyzing a single or multiple detection targets by analyzing the separated high-resolution fluorescence images,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The image sensor is formed on top of the microlens array,
The separation distance between the image sensor and the microlens array is 5 mm or less,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The distance between the image sensor and the filter unit is 5 mm or less,
The gap between the measurement sample and the filter unit is 5 mm or less,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The thickness of the transparent substrate is 5 mm or less,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The transparent substrate includes at least one of glass, transparent polymer, and transparent oxide.
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The filter unit includes a single or multiple bandpass filters,
The band-pass filter transmits the fluorescence expressed in the measurement sample and blocks the light of the lighting unit,
Ultra-thin microscope based on microlens array.
According to clause 11,
The bandpass filter includes a color filter, a plasmonic filter, or both.
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The transparent substrate is,
Transparent base substrate; and a transparent layer formed on the transparent base substrate;
Including,
A microlens array is formed on the transparent layer,
The transparent layer includes transparent oxide,
Ultra-thin microscope based on microlens array.
According to clause 13,
a first layer formed between the transparent base substrate and the transparent layer; and a second layer formed on the transparent layer corresponding to the position of the first layer,
The first layer and the second layer each include a light absorption film, a blocking film, or both.
Ultra-thin microscope based on microlens array.
According to clause 14,
The first layer is inserted into the transparent layer,
The first layer and the second layer are each single or multiple layers,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The microlens array-based ultra-thin microscope monitors the measurement sample in the microfluidic system,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The microlens array-based ultra-thin microscope is for on-site diagnosis,
Diagnosing two or more diseases,
Ultra-thin microscope based on microlens array.
According to paragraph 1,
The microlens array-based ultra-thin microscope has an illumination unit that irradiates light to the measurement sample.
which further includes,
Ultra-thin microscope based on microlens array.

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