WO2011115445A2 - Biopuce - Google Patents

Biopuce Download PDF

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Publication number
WO2011115445A2
WO2011115445A2 PCT/KR2011/001878 KR2011001878W WO2011115445A2 WO 2011115445 A2 WO2011115445 A2 WO 2011115445A2 KR 2011001878 W KR2011001878 W KR 2011001878W WO 2011115445 A2 WO2011115445 A2 WO 2011115445A2
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layer
nanoparticle layer
biochip
metal nanoparticle
metal
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PCT/KR2011/001878
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English (en)
Korean (ko)
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WO2011115445A3 (fr
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김상효
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경원대학교 산학협력단
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Priority claimed from KR1020110023941A external-priority patent/KR101288244B1/ko
Application filed by 경원대학교 산학협력단 filed Critical 경원대학교 산학협력단
Priority to US13/635,060 priority Critical patent/US9081005B2/en
Publication of WO2011115445A2 publication Critical patent/WO2011115445A2/fr
Publication of WO2011115445A3 publication Critical patent/WO2011115445A3/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors

Definitions

  • the present invention relates to a biochip that can qualitatively and quantitatively analyze a biomaterial without a tag by including a metal nanoparticle layer on a cell array substrate.
  • Biochip is a hybrid device made of a conventional semiconductor chip by combining biological organisms such as enzymes, proteins, antibodies, DNA, microorganisms, animal and plant cells and organs, nerve cells and organs, nerve cells, and inorganic materials such as semiconductors and glass. (Hybrid device). By utilizing the inherent functions of biomolecules and mimicking the functions of living organisms, it is characterized by diagnosing infectious diseases, analyzing genes, and acting as a new information processing new functional device.
  • biological organisms such as enzymes, proteins, antibodies, DNA, microorganisms, animal and plant cells and organs, nerve cells and organs, nerve cells, and inorganic materials such as semiconductors and glass.
  • Biochips can be classified into DNA chips, RNA chips, protein chips, cell chips, and neuron chips according to the degree of biomolecules and systemization, and are automatically analyzed by small-scale integration of sample pretreatment, biochemical reaction, detection, and data interpretation. It can be broadly defined, including biosensors capable of detecting and analyzing various biochemicals such as lab on a chip.
  • biochip analysis is mainly performed by labeling analytical samples with tags such as fluorescent materials and measuring emission wavelengths and intensities emitted by externally excited light.
  • tags such as fluorescent materials
  • the detection method is complicated and an expensive analysis apparatus is required, which is expensive, and the emission efficiency of the phosphor is low and the lifetime is relatively short, thus making it difficult to measure for a long time.
  • the present invention is to provide a biochip that is easy to use and reusable since the detection method is relatively simple without using a separate tag in analyzing the biomaterials qualitatively or quantitatively.
  • the present invention provides a cell array comprising a substrate, a metal nanoparticle layer attached on the substrate and a dielectric layer attached on the metal nanoparticle layer in each cell; And a CMOS image sensor (CIS).
  • a CMOS image sensor CIS
  • the present invention also provides a cell array comprising a substrate, a metal nanoparticle layer attached on the substrate, a dielectric layer attached on the metal nanoparticle layer in each cell, and a filling layer attached on the metal nanoparticle layer without the dielectric layer; And a CMOS image sensor.
  • the biochip according to the present invention which includes a metal nanoparticle layer on a cell array substrate and uses a CMOS image sensor, does not require a separate tag and has a simple detection method. Can provide.
  • FIG. 1 is a view showing the structure of a cell array according to an embodiment of the present invention.
  • FIG. 2 is a view showing the structure of A-A 'cross section of FIG.
  • FIG 3 is a view showing the structure of a biochip according to an embodiment of the present invention.
  • FIG. 4 is a view showing a state in which an analyte is coupled to a dielectric layer of a biochip according to an embodiment of the present invention.
  • Figure 5 is a graph showing the results of analyzing the change in the number of photons by the binding of the primary and secondary antibodies using a biochip according to another embodiment of the present invention by the digital output number.
  • Figure 6 is a graph showing the results of analyzing the binding efficiency of the protein on the basis of the results of FIG.
  • FIG. 7 is a graph showing the results of analyzing the binding efficiency of the protein according to the thickness of the indium nanoparticle layer based on the result of FIG.
  • FIG. 8 is a photograph showing the results of analyzing the shape of the cell array surface before and after the antibody treatment by FE-SEM.
  • FIG. 9 is a photograph showing the results of analyzing the shape of the cell array surface before and after the antibody treatment by AFM.
  • 10 is a photograph showing the results of observing the antigen-antibody reaction with a fluorescence microscope.
  • cell array substrate 20 metal nanoparticle layer
  • cell array 200 CMOS image sensor
  • CMOS sensor lens 220 photodiode
  • the present invention provides a cell array comprising a substrate, a metal nanoparticle layer attached to the substrate, and a dielectric layer attached to the metal nanoparticle layer in each cell; And a CMOS image sensor.
  • cell refers to a space in which a sample material to be analyzed can react
  • cell array refers to an aggregate in which a plurality of cells are arranged.
  • the cell array may be each cell is divided into separate compartments, or may be formed by separately attaching the dielectric layer on the metal nanoparticle layer corresponding to each cell without a separate compartment.
  • Biochip includes a metal nanoparticle layer attached on the substrate of the cell array, so that the biomaterials do not have a separate tag, such as indium slide immunoassay (ISI)
  • ISI indium slide immunoassay
  • the type and amount of the biomaterial to be detected can be easily analyzed.
  • the binding prevents the photons entering the CMOS image sensor, and thus the number of photons absorbed by the CMOS lens is reduced and the light intensity is reduced. Analysis is possible.
  • the type of light source that can be used is not particularly limited, but according to the present invention, there is an advantage that the biomaterial can be easily qualitatively and quantitatively analyzed even using a visible light source.
  • the present invention includes a CMOS image sensor (CIS) as a sensor that detects an optical signal generated from a cell and converts it into a digital electrical signal, and thus the driving method is simple and can be implemented by various scanning methods. Processing circuits can be integrated on a single chip, allowing for miniaturization of the product.
  • the CMOS process technology can be used interchangeably to reduce the manufacturing cost, the power consumption is also very low, it is easy to apply to products with limited battery capacity.
  • CMOS image sensor The principle of CMOS image sensor is as follows. There is a single photodiode in the sensor that absorbs light and converts it into other signals in this region, which is based on the photoelectric effect principle. When photons accumulate in the form of charge and are converted from electrons, this amount is proportional to the number of photons detected by touching the CMOS image sensor. Accumulated charges are amplified in the form of analog voltages, which are converted into digital numbers. The numbers displayed on the digital output are proportional to the number of photons detected by the image sensor. If other material on the surface of the image sensor interferes with photon passing, the number of digital outputs will decrease.
  • the fabrication of the biochip by combining the cell array and the CMOS image sensor may be performed by a method known in the art, and may be appropriately selected by those skilled in the art.
  • the cell array and the CMOS image sensor may be formed by separate processes on different substrates and then packaged to manufacture a single biochip.
  • the cell array and the CMOS image sensor are formed by different manufacturing processes, and then packaged into one biochip using a multi-stack package process used in a semiconductor device manufacturing process, and the like, to be completed. May be, but is not limited thereto.
  • the type of substrate in the cell array is not particularly limited, such as a glass substrate, a silicon substrate, a plastic substrate, a compound semiconductor substrate, a quartz substrate, and a sapphire substrate, and various substrates generally used in biochips may be used.
  • the metal nanoparticle layer attached on the substrate of the cell array may be an indium or gold nanoparticle layer.
  • the present invention is not limited thereto, and is understood to include various metal nanoparticle layers known in the art.
  • the size of the metal nanoparticles may vary depending on the type of biomaterial used as the dielectric, but may generally have a diameter of several tens of nanometers to several hundred nanometers. This is because the metal nanoparticles become opaque as the particles become larger than the wavelength of visible light due to the size of the biomaterial after the attachment of the biomaterial.
  • the size of the metal nanoparticles and the thickness of the metal nanoparticle layer attached on the substrate affects the bonding efficiency of the biomaterial, and thus the sensitivity of the CMOS sensor may be changed. That is, as a result of measuring the signal according to the binding of the primary antibody and the secondary antibody using gamma-interferon as a dielectric, the thickness of the metal nanoparticle layer is 10 nm, 20 nm and the diameter of the metal nanoparticle is 70-100 nm, respectively. , In the range of 150-200 nm, it was confirmed that the high sensitivity of the antibody binding high sensitivity.
  • the size of the metal nanoparticles may be 60 ⁇ 300 nm, 60 ⁇ 250 nm, 70 ⁇ 250 nm or 70 ⁇ 200 nm.
  • the thickness of the metal nanoparticle layer may be 5 ⁇ 30 nm, 5 ⁇ 25 nm, 7 ⁇ 30 nm, 7 ⁇ 25 nm, 9 ⁇ 30 nm or 9 ⁇ 25 nm.
  • the evaporation of a metal, such as indium or gold, on a substrate in a vacuum causes the metal atoms to condense onto small particles on the substrate.
  • the size of the metal particles may be determined according to the amount of metal evaporated or the temperature of the substrate.
  • Attachment of the metal nanoparticles may be performed using a method known in the art, but is not limited thereto.
  • Giaever et al. A New Assay for Rheumatoid Factor, CLINICAL CHEMISTRY, Vol. 30, no.
  • indium metal Indium Corp. of America, Utica, NY 13503 was deposited in nanoparticle form by vacuum deposition under reduced pressure of 10 -6 mmHg on a glass substrate of a reduced-pressure evaporator. You can. Usually, at 350 ° C.
  • the size of the metal particles may be deposited to a diameter of several tens of nanometers to several hundred nanometers by vacuum deposition at a pressure of about 10 ⁇ 8 mmHg to 10 ⁇ 4 mmHg for 1 to 10 minutes under reduced pressure. It is not limited.
  • the dielectric layer attached to the metal nanoparticle layer in each cell may be a layer consisting of a biomaterial selected from the group consisting of DNA, RNA, protein, enzyme, antigen, antibody, peptide, carbohydrate and lipid.
  • a biomaterial selected from the group consisting of DNA, RNA, protein, enzyme, antigen, antibody, peptide, carbohydrate and lipid.
  • an antigen protein that specifically binds to an antibody protein to be analyzed may be used as a probe protein to attach a dielectric layer on the metal nanoparticle layer in each cell.
  • the analyte to be analyzed using the biochip according to the present invention is a substance that specifically binds to a biomaterial used as a dielectric layer, and includes, for example, DNA, RNA, protein, enzyme, antigen, antibody, peptide, carbohydrate and lipid. Can be selected from the group.
  • the biomaterial is attached to the slide using a solution containing the biomaterial.
  • the biomaterial is attached as a single layer on the metal nanoparticle layer, and the attached biomaterial acts as a dielectric layer.
  • the metal nanoparticle layer is covered with the dielectric layer, scattering of light by the metal nanoparticles increases, and the intensity of transmitted light changes so that the portion where the dielectric layer is attached can be identified qualitatively.
  • the cell array may further include a filling layer attached on the metal nanoparticle layer having no dielectric layer. That is, by attaching a separate filling layer to the remaining portion of the metal nanoparticle layer not covered with the dielectric layer, the substrate, the metal nanoparticle layer attached on the substrate, the dielectric layer and the dielectric layer attached on the metal nanoparticle layer in each cell A cell array comprising a charge layer attached over the free metal nanoparticle layer; And a CMOS image sensor.
  • the filling layer may be attached to the metal nanoparticle layer only as a single layer without being attached to the dielectric layer. That is, the surface of the substrate may be made uniform by attaching an inert protein that does not bind to the biomaterial corresponding to the dielectric layer on the remaining surface except the dielectric layer on the substrate.
  • the filling layer may be a metal protein, but is not limited thereto.
  • Metal protein refers to a protein complex in combination with metal ions such as iron, copper, zinc.
  • the metal protein may be, for example, aldolase, but is not limited thereto.
  • qualitative and quantitative analysis of the biomaterial may be performed by contacting the analytical sample on a cell array having uniform surface properties. For example, if an antibody protein in an assay sample specifically binds to an antigen protein in a specific cell of a specific biochip by an antigen antibody reaction, a change in light scattering at the corresponding site occurs, and the antibody protein does not bind and thus no light scattering change. It can be qualitatively identified from the rest of the site so that the type of antibody protein in the sample can be easily qualitatively analyzed. In addition, as the amount of bound protein increases, the intensity of light that transmits through the cell array decreases. Thus, the amount of bound protein can be quantified by measuring the change in intensity of transmitted light using a CMOS image sensor. In addition, quantitative analysis is possible by estimating the amount of protein through visual inspection.
  • biochip according to the present invention may be reused after washing the surface of the cell array after performing the above protein analysis to desorb the antibody protein bound to the probe protein.
  • FIG. 1 is a view showing the structure of a cell array according to an embodiment of the present invention.
  • the cell array 100 includes a substrate 10, a metal nanoparticle layer 20 attached on the substrate, and a dielectric layer 30 attached on the metal nanoparticle layer in each cell.
  • FIG. 1 illustrates that the cell array 100 is formed by attaching the dielectric layer 30 to a position corresponding to each cell without separately dividing each cell, it is also possible to divide each cell into separate compartments.
  • FIG. 2 shows the structure of A-A 'cross section of FIG.
  • FIG. 2 shows a fill layer 40 additionally attached over the metal nanoparticle layer 20 without the dielectric layer 30.
  • the dielectric layer 30 and the filling layer 40 are attached as a single layer on the metal nanoparticle layer 20 to form a uniform surface layer.
  • FIG. 3 shows a structure of a biochip according to an embodiment of the present invention.
  • FIG. 1 illustrates a biochip in which the CMOS image sensor 200 is coupled to the cell array 100 of FIG. 1.
  • FIG. 4 shows a state in which an analyte is bound to a dielectric layer of a biochip according to the present invention.
  • the analyte When the analyte is contacted with the cell array 100 and the analyte 50 specific to the biomaterial, which is the dielectric layer 30 in a particular cell, changes in the intensity of light passing through the cell from the light source occurs.
  • the change in the intensity of light is converted into an electrical signal by the CMOS image sensor 200 and displayed on a display so that the type and amount of the analyte included in the analytical sample may be analyzed qualitatively and quantitatively.
  • the biomaterial may be qualitatively or quantitatively analyzed by comparing the light intensity of each control cell to which the analyte is not bound to each cell to which the analyte is bound. .
  • Indium beads (Sigma Aldrich) and thermal evaporator (Daeki Hi-Tech) were used to deposit indium nanoparticles of different sizes on the surface of the glass substrate.
  • Various factors were adjusted to produce an indium nanoparticle layer with the desired thickness and size.
  • This example was carried out under a gas pressure of 0.3 ⁇ 1 Pa, the chamber discharge pressure was 10 -6 Torr using argon gas, the total gas pressure was obtained by operating a mass flow controller.
  • the distance between the target and the substrate was maintained at about 50-80 mm.
  • the speed of the thermal evaporator was adjusted to 0.05 ⁇ 0.1 ⁇ / s and the thermal evaporator was stopped when the desired thickness was reached.
  • the thickness of the metal nanoparticle layer was obtained at 5, 10, 20, and 40 nm, respectively, and the diameters of the metal nanoparticles were also different from 30 to 50, 70 to 100, 150 to 200, and 350 to 400 nm, respectively.
  • the CMOS image sensor uses an 110,000-pixel single chip used in ordinary mobile phone cameras.
  • This CMOS image sensor has a 376 x 314 pixel array and is on-chip (integrated circuitry on a semiconductor) of a 10-bit ADC. Siliconfile Technologies Inc. Received from
  • Recombinant gamma-interferon used as the genome primary polyclonal gamma-interferon antibody (1 ° Ab) and secondary antibody (FITC conjugated goat anti-globulin: 2 ° Ab) was obtained from Abcam. All solutions and buffers were prepared and prepared with distilled water. PBS containing 138 mM NaCl and 2.7 mM KCl and having an acidity of pH 7.4 was used as a buffer.
  • Gamma-interferon was diluted with 0.85% w / v NaCl solution and a final concentration of 5 ⁇ g / ml was prepared.
  • Primary antibodies were diluted with 1% BSA solution and final concentrations were prepared at 1 ⁇ g / ml, 1 ng / ml, 1 pg / ml and 1 fg / ml, respectively.
  • the secondary antibody was also diluted with the primary antibody and the final concentration was diluted to 20 ⁇ g / ml.
  • the backlight brightness of the CMOS image sensor was adjusted to the highest value by manually adjusting the integration time and analogue value.
  • the maximum intensity of the light was calibrated; Thereafter, photons were measured while sequentially applying light to the cell array to which the antigen antibody was bound.
  • Example 1 the substrates coated with indium nanoparticles to have thicknesses of 5, 10, 20, and 40 nm, respectively, were cut into 4 pieces (16 pieces in total) and washed with distilled water, and each size was 5 ⁇ 5 mm. All substrates were exposed to the lens of the CMOS image sensor for the calculation of the input and output of photons.
  • the 16 washed substrates were immersed in gamma-interferon antigen (5 ⁇ g / ml concentration) and incubated at room temperature for 60 minutes. Subsequently, the substrates were washed with distilled water and dried. All 16 substrates were exposed to CMOS image sensors for photon count analysis after antigen adsorption.
  • One of the substrates each having a specific thickness was taken and placed in a Petri dish containing primary antibodies having concentrations of 1 ⁇ g / ml, 1 ng / ml, 1 pg / ml, and 1 fg / ml, and optionally shaken for 3 hours. All the substrates were washed with distilled water and dried using an air compressor to separate primary antibodies that did not adsorb to the substrate. All substrates to which the primary antibodies were attached were incubated in a shaded secondary antibody at 20 ⁇ g / ml for one hour. Subsequently, the substrates were washed with distilled water and then dried for photon analysis due to binding of the secondary antibody. Each substrate was analyzed by exposure to a CMOS image sensor.
  • the number of photon absorption observed through the CMOS lens on the substrate coated with the indium nanoparticle layer was reduced by the sequential binding of the antigen and the primary and secondary antibodies.
  • (A), (B), (C) and (D) show experimental results using a substrate coated with an indium nanoparticle layer with a thickness of 5, 10, 20 and 40 nm, respectively (A), (B), ( In both C) and (D), it can be seen that the number of digital outputs is significantly reduced as the antigen (Ag), the primary antibody (1 ° Ab), and the secondary antibody (2 ° Ab) bind to the substrate.
  • the number of digital outputs from the CMOS sensor is proportional to the number of photons detected by the CMOS image sensor. This decrease in the number of photons is due to the reduction of the intensity of light absorbed from the CMOS lens because the antigen and the antibody proceed to bind to prevent photons entering the CMOS image sensor.
  • biochip according to the present invention it can be seen that it is possible to detect the antigen-antibody reaction up to a concentration of femto unit of 1 fg / ml.
  • Example 3 Measurement of the binding efficiency of the protein according to the thickness change of the metal nanoparticle layer
  • Example 6 is a graph showing the efficiency of binding to the indium nanoparticle layer having a thickness of 5, 10, 20, 40 nm, respectively, antigen and the primary antibody in the experimental results of Example 2.
  • the relative binding efficiency of the antigen was obtained by subtracting the digital output number of the indium nanoparticle-antigen binding from the digital output number of the indium nanoparticle layer.
  • the relative binding efficiency of the primary antibody was obtained by subtracting the digital output number of indium nanoparticle-antigen-1 antibody binding from the digital output number of indium nanoparticle-antigen binding, and the relative binding efficiency of the secondary antibody.
  • the digital output value at the indium nanoparticle-antigen-primary antibody-secondary antibody binding was subtracted from the digital output number at the silver indium nanoparticle-antigen-primary antibody binding.
  • the binding efficiency of the primary antibody is not only dependent on the concentration, but also affected by the degree of binding of the antigen and the metal nanoparticle layer. Since the antigens were used at the same concentration in all experiments, theoretically the amount of antigen and metal nanoparticle binding should be the same and uniform in all cases. However, the indium nanoparticle layer having a thickness of 10 nm and 20 nm was significantly lower than that of the indium nanoparticle layer having a thickness of 5 nm and 40 nm, whereas the binding efficiency of the antigen was about 3 or 6. And it can be seen that the binding efficiency of the antigen and the metal nanoparticle layer also affects the binding efficiency of the primary and secondary antibodies.
  • Figure 7 shows the binding efficiency of the protein and the indium nanoparticle layer of each thickness, regardless of the concentration of the primary antibody in order to confirm the optimal conditions of binding efficiency with the gamma-interferon antigen. This is the result of averaging the coupling efficiency of FIG. 6 for each thickness.
  • the coupling efficiency was high in the range of 10 to 12, but in the case of the indium nanoparticle layer having a thickness of 5 nm and 40 nm, the efficiency was as low as 3 to 6.
  • the synthesis of the above experimental results can be seen that the intimacy of the indium nanoparticle layer and the antigen depends on the diameter of the indium nanoparticles and the thickness of the nanoparticle layer.
  • the results of this experiment show that the diameter of indium nanoparticles with 10 nm and 20 nm thickness is suitable for binding to gamma-interferon antigen, and for this reason, the diameter of indium nanoparticles with thickness of other 5 nm and 40 nm is 1 It seems to exhibit good binding efficiency with primary antibodies.
  • the results of Examples 2 and 3 show that the biochips according to the present invention can detect antigen-antibody interactions at various concentration ranges, and are particularly sensitive biochips capable of detecting concentrations up to 1 fg / ml. .
  • the antigen-antibody interaction can be analyzed most sensitively when the thickness of the metal nanoparticle layer formed on the substrate is about 10-20 nm.
  • the metal nanoparticle layer (Bare sub) before the antigen treatment mostly forms uniform particles, whereas the primary antibody is ng / ml (Sub / Ag-Ab (ng)) after antigen treatment.
  • the primary antibody is ng / ml (Sub / Ag-Ab (ng)) after antigen treatment.
  • ng / ml
  • ⁇ g / ml
  • ⁇ g / Ag-Ab
  • the metal nanoparticles were connected to each other to form large particles.
  • the metal nanoparticle layer having a uniform and smooth surface is changed to a rough surface due to antigen-antibody interaction.
  • the largest change occurred in the 10 nm and 20 nm thick metal nanoparticle layer, which is the same as the previous experiments with the CMOS image sensor.
  • Bio-Atomic Forece Microscope (AFM; Nanowizard II, JPK instrument) was used to observe the surface roughness of the protein adsorbed onto the indium nanoparticle layer (analyzed by 2 x 2 um area of all substrates).
  • the metal nanoparticle layer (Bare sub) before the antigen treatment mostly forms uniform particles, whereas the primary antibody is ng / ml (Sub / Ag-Ab (ng)) after antigen treatment.
  • the primary antibody is ng / ml (Sub / Ag-Ab (ng)) after antigen treatment.
  • ⁇ g / ml Sub / Ag-Ab ( ⁇ g)
  • the metal nanoparticles were connected to each other to form large particles.
  • the largest change occurred in the 10 nm, 20 nm thick section of the metal nanoparticle layer, which is consistent with the results of Example 4-1.
  • the surface roughness value (RMS) after adding an antigen, a primary antibody, and a secondary antibody to the indium nanoparticle layer was measured.
  • the roughness value increased as the antigen, the primary antibody, and the secondary antibody were sequentially added, and in particular, the roughness difference due to the antigen-antibody interaction in the 10 nm and 20 nm thick indium nanoparticle layers was increased. It is obvious.
  • Fluorescence microscopy was used to determine the fluorescent intensity of indium nanoparticle-antigen substrates treated with gamma-interferon primary antibody and FITC conjugated goat anti-globulin secondary antibody.

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Abstract

L'invention concerne une biopuce comprenant une couche nanoparticulaire métallique sur un substrat de matrice de cellules, ce qui permet une analyse quantitative et qualitative simple de biomatéraux même sans une étiquette additionnelle. La biopuce selon l'invention comprenant une couche nanoparticulaire métallique sur un substrat de matrice de cellules qui n'a pas besoin d'utiliser une étiquette additionnelle lorsqu'elle utilise un capteur d'image CMOS, est pratique à utiliser grâce à un simple procédé de détection. Elle est en outre réutilisable et économique.
PCT/KR2011/001878 2010-03-19 2011-03-18 Biopuce WO2011115445A2 (fr)

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US13/635,060 US9081005B2 (en) 2010-03-19 2011-03-18 Biochip

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KR10-2010-0024646 2010-03-19
KR20100024646 2010-03-19
KR1020110023941A KR101288244B1 (ko) 2010-03-19 2011-03-17 바이오칩
KR10-2011-0023941 2011-03-17

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10267841A (ja) * 1997-03-24 1998-10-09 Kokuritsu Shintai Shogaisha Rehabilitation Center Souchiyou 表面プラズモン共鳴センシングデバイス
JP2005291966A (ja) * 2004-03-31 2005-10-20 Shimadzu Corp 表面プラズモン共鳴を利用した測定装置
KR20100002960A (ko) * 2008-06-30 2010-01-07 재단법인서울대학교산학협력재단 표면 플라즈몬 공명 센서칩, 그 제조 방법, 표면 플라즈몬공명 센서 시스템 및 그를 이용한 분석 대상 물질 검출방법
KR20100043432A (ko) * 2008-10-20 2010-04-29 삼성전자주식회사 바이오칩용 광검출 장치

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10267841A (ja) * 1997-03-24 1998-10-09 Kokuritsu Shintai Shogaisha Rehabilitation Center Souchiyou 表面プラズモン共鳴センシングデバイス
JP2005291966A (ja) * 2004-03-31 2005-10-20 Shimadzu Corp 表面プラズモン共鳴を利用した測定装置
KR20100002960A (ko) * 2008-06-30 2010-01-07 재단법인서울대학교산학협력재단 표면 플라즈몬 공명 센서칩, 그 제조 방법, 표면 플라즈몬공명 센서 시스템 및 그를 이용한 분석 대상 물질 검출방법
KR20100043432A (ko) * 2008-10-20 2010-04-29 삼성전자주식회사 바이오칩용 광검출 장치

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