• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a device for quantifying binding and disassociation kinetics in the molecular interaction of small molecular biomaterials with high sensitivity almost without the effect of a change in refractive index resulting from a buffer solution by making the incident light fall on the binding layer of a biomaterial , which is formed on a thin dielectric layer, so that the polarized incident light satisfies a non-reflective state of p-waves and a quantification method using the same.
    公开号:SE1200214A1
    申请号:SE1200214
    申请日:2010-10-29
    公开日:2012-04-10
    发明作者:Hyun Mo Cho；Gal Won Che；Yong Jai Cho
    申请人:Korea Res Inst Of Standards；
    IPC主号:
    专利说明:

    [10] [10] Problems with the conventional SPR sensor for biomaterial analysis are described below with reference to Figs. 3 and 4. Fig. 3 is a diagram showing the measurement of the ellipsometric constant Lp using the SPR sensor, showing a similar characteristics as with conventional reflectivity. As shown in Fig. 3, the thin metal layer 20 was formed of a thin Au layer of 50 nm thickness, and a light source 40 having a wavelength of 633 nm was used. In addition, a bonding layer was measured to a thickness of 0 to 1 nm. Furthermore, the bonding layer was measured to be 1.45 in refractive index n, and the buffer solution 34 had a refractive index n of 1.333 and 1.334.
    [11] [11] According to the principles of the conventional SPR sensor, the magnitude of an offset in the SPR angle over time, showing a minimum reflectance, is measured by measuring the reflectance or the ellipsometric constant Lp from which a change in the intensity of the reflected light can be known. Here, if the surface plasmon resonance phenomenon is satisfactory, the reflectivity or the ellipsometric constant Lp has a minimal value, and the SPR angle is close to 59 ° as shown in Fig. 3. It can also be seen that the ellipsometric constant Lp moves to the right with a increase in the thickness of the bonding layer and also an increase in the refractive index of the buffer solution 34. Fig. 3 shows a comparison of a case in which the biomaterials having a refractive index of 1.45 bind about 1 nm and a case in which it does not there was some binding of biomaterial and there was a change in the SPR angle only when the refractive index of the buffer solution 34 was changed from 1.333 to 1.334. Av fi g. 3 it appears that the two cases show a similar change in the SPR angle. In other words, only pure binding and disassociation characteristics from which a change in the refractive index of the buffer solution has been removed need to be measured, but it can be seen that when binding and disassociation characteristics of biomaterials are measured, a problem in measurement results arises. due to a change in the refractive index of the buffer solution.
    [12] [12] Fig. 4 is a graph illustrating a conventional problem in which the binding and disassociation kinetics built into the samples, which appear in a process where the samples bind and disassociate, and a change in refractive index, which results from a buffer fourth solution is mixed together. Fig. 4 (a) is a diagram showing in the samples 32 existing binding and disassociation concentrations and which appear in the binding and disassociation process. Fig. 4 (b) is a diagram showing a change in the measurement results of the SPR sensor resulting from a change in refractive index of the buffer solution 34.
    [13] [13] On the other hand, to correct a change in refractive index of the buffer solution 34 and to prevent errors resulting from diffusion between the samples 32 and the buffer solution 34, a correction method using a carefully prepared valve device and a carefully designed air injection device and two or more ducts used as reference ducts. However, this method is difficult to use to distinguish a change in the SPR angle resulting from a change in the refractive index of the buffer solution 34 and a change in the SPR angle resulting from pure binding and dissociation characteristics, and the changes can always serve as measurement error factors. Accordingly, the conventional SPR sensor has a fundamental problem in measuring the binding and disassociation characteristics of a material having a low molecular weight, such as a small molecule, due to the limitations of the measurement method, as described above.
    [14] [14] Furthermore, the conventional SPR sensor requires a high manufacturing cost for the sensor because it uses the thin metal layer made of precious metal, such as gold Au or silver (Ag), for surface plasmon resonance. In addition, the thin metal layer 20 is problematic in that a refractive index has a sharp variation because the surface roughness is not uniform depending on the manufacturing process and quantitative measurement for biomaterial is difficult due to unstable optical characteristic.
    [15] Accordingly, the invention has been accomplished in view of the above problems which exist according to the prior art, and an embodiment of the present invention is to provide an apparatus and a method for quantifying the binding and dissociation kinetics of molecular interaction, which is not affected by a change in refractive index resulting from a buffer solution in a immersion in a liquid environment of microfluidic pathways and which can withstand an increased measurement sensitivity due to the use of a thin metal layer with unstable light characteristics.
    [16] [16] Another embodiment of the present invention is to provide an apparatus and method for quantifying the binding and disassociation kinetics of molecular interaction, which is capable of increasing the reliability and efficiency of binding and disassociation kinetics studies by using a microflow pathway structure optimized for small molecule biomaterial analysis.
    [17] [17] According to one embodiment of the present invention, there is provided an apparatus for quantifying the binding and disassociation kinetics of molecular interaction, comprising a structure 100 for microfluidic pathways, comprising a substrate 110, a substrate 120 formed on the substrate 110 and made of a semiconductor or of a dielectric material, a thin dielectric layer 130 formed on the substrate 120, an enveloping unit 140 which is designed so as to have an incident window 142 and a reflection window 144, respectively, arranged on one and the other side and arranged on the substrate 110, and microflow paths 150 formed in the substrate 110 and between the substrate 110 and the envelope assembly 140; a sample injection unit 200 for forming a bonding layer 160 of samples on the thin dielectric layer 130 by injecting a buffer solution 210, comprising the samples of a biomaterial into the microfluidic pathways 150; a polarization generating unit 300 for irradiating incident light, polarized through the incident window 142, to the bonding layer 160 at an angle of incidence 6 which satisfies a state of non-reflective p-wave; and a polarization detection unit 400 for detecting a change in the polarization of reflected light in the bonding layer 160 which is incident through the reflection window 144. 10 15 20 25 30 35 6
    [18] [18] The thin dielectric layer 130 comprises a semiconductor oxide layer or a glass layer made of a transparent material. It is preferred that the thin dielectric layer 130 have a thickness of 0 to 1000 nm.
    [19] [19] Further, the structure 100 of microflow paths comprises a plurality of inlet paths 152 and a plurality of outflow paths 154 formed on one and the other side of the substrate 110, respectively, and the microflow paths 150 of the plurality of channels are configured to have a number of barrier ribs. 146 formed on an inside of the enveloping unit 140 and so that they connect the inflow paths 152 and the outflow paths 154, respectively.
    [20] [20] Further, the structure 100 of microflow paths forms the microflow path 150 for a single channel, and a plurality of different self-assembled monolayers 132 to which the samples are bonded are further formed on the thin dielectric layer 130.
    [21] [21] Further, each of the incident window 142 and the reflection window 144 of the envelope unit 140 have a curved shell shape with a predetermined curvature, and the incident light and the reflecting light incident on the incident window 142 and the reflection window 144, respectively, in a vertical angle of inclination. or at an almost vertical angle with a magnitude such that a polarized state of each of the incident light and the reflecting light does not change much.
    [22] [22] Furthermore, each of the incident window 142 and the reflection window 144 of the envelope unit 140 have a flat sheet shape. The incident light and the reflecting light fall on the incident window 142 and the reflection window 144, respectively, at a vertical angle or at an almost vertical angle with a magnitude such that a polarized state of each of the incident light and the reflecting light does not change. so much.
    [23] [23] Furthermore, the casing unit 140 is integrally made of glass or a transparent synthetic resin material.
    [24] [24] Further, the bonding layer 160 is a layered layer, comprising a self-assembled monolayer 132 suitable for bonding properties of various biomaterials, an oxidizing material, and various biomaterials, including molecules bound to the fixing material.
    [25] [25] Further, the polarization generating unit 300 comprises: a light source 310 for radiating predetermined light, and a polarizer 320 for polarizing the radiated light. Here, the light source 310 emits monochromatic light or white light, and it may be a laser or a laser diode, which has a wavelength variable structure.
    [26] [26] Further, the polarization generating unit 300 may comprise at least one of: a collimator lens 330 for providing parallel light to the polarizer 320, and a first compensator 350 for phase delay of the polarized components of the incident light. 7 set. Here, the polarizer 320 and the first compensator 350 may be rotatably designed or they may also be equipped with polarization modulating means.
    [27] [27] Further, the polarization detection unit 400 may include an analyzer 410 configured to polarize the reflected light, a photodetector 420 configured to obtain predetermined data by detecting the polarized reflected light, and an operating processor 430 electrically connected to the photodetector 420 and is performed to induce quantified values based on optical data. Furthermore, the operating processor 430 can induce the quantified values, including a binding concentration, and a disassociation constant of the samples, by finding an ellipsometric constant Lp or A with respect to a phase difference of an ellipsometry.
    [28] [28] Further, the polarization detector unit 400 may further comprise at least one of a second compensator 440 for phase delay of the polarized components of the reflected light and a spectroscope 450 for making a spectrum of the reflected light.
    [29] [29] According to another aspect of the present invention, there is provided a method for quantifying the binding and disassociation kinetics of molecular interaction, comprising a first step S100 of a sample spray unit 200 with injection of a buffer solution 210, including samples of small molecular biomaterials, to microflow paths 150 of a structure 100 of microflow paths; a second stage S200 in which samples are bonded to a thin dielectric layer 130 of the microflow path structure 100, so as to form a bonding layer 160, a third stage S300 of a polarization generating unit 300 which polarizes predetermined light and causes the polarized light to fall into the bonding layer 160 at an angle of incidence to satisfy a non-reflective state of p-waves through an incident window 142 of the structure 100 of microflow paths; a fourth step S400 in which reflected light of the bonding layer 160 is incident on a polarization detection unit 400 through a reflection window 144 of the structure 100 of microflow paths; and a fifth step S500 wherein the polarization detecting unit 400 detects a polarization state of the reflected light using an ellipsometry or a reflectometry.
    [30] [30] Further, in the first step S100, the buffer solution 210 including the samples of different concentrations is injected into the respective microfluidic paths 150 of the structure 100 by microfluidic paths comprising multiple channels.
    [31] [31] Further, in the second step S200, the samples are bonded to a plurality of different self-assembling monolayers 132 formed on the thin dielectric layer 130, so as to form the various bonding layers 160. 10 15 20 25 30 35 8
    [32] [32] Further, the fifth step S500 comprises a step of an analyzer 410 polarizing the reflected light, a step of obtaining a predetermined optical data by detecting optical data by detecting the polarized reflected light, and a step of inducing a quantized processor 430. values, including a binding concentration, a binding constant and a disassociation constant of the samples, by finding an ellipsometric constant w or A of the ellipsometry based on these optical data.
    [33] [33] Beneficial effects of the invention
    [34] [34] As described above, in accordance with the device and method for quantifying the binding and disassociation kinetics of molecular interaction according to the invention, a thin dielectric layer is used instead of a thin metal layer for binding the samples.
    [35] [35] Furthermore, according to the present invention, an ellipsometry and a reflectometry are used in a non-reflective state of p-waves, and incident light having a high amount of light is provided by using a laser or a laser diode. Consequently, the signal-to-noise ratio is reduced, whereby a highly sensitive measurement is achieved. Furthermore, there is an advantage in that when an ellipsometry is used, a quantitative measurement using an amplitude ratio Lp is possible in a non-reflective state of p-waves and a highly sensitive measurement is possible via the measurement of a phase difference A at an angle which is not non-reflective state of p-wave
    [36] [36] Furthermore, the microflow path structure of the present invention includes microflow paths optimized for the analysis of small molecule biomaterials and a multiple channel or a single channel composed of a plurality of self-assembled monolayers. Consequently, different experimental conditions can be provided in which samples with varying concentrations are injected into the multichannel micro vä pathways or the degree of binding of the self-assembled monolayers is varied. Consequently, there is an advantage in that the efficiency of analysis experiments on biomaterials can be improved.
    [37] [37] Furthermore, the present invention can be used for various industrial fields, such as bio, medical treatment, food and an environment since highly sensitive measurement for biomaterial can be performed in a non-signing manner in an environment of microfluidic immersion pathways. 10 15 20 25 30 35 9
    [38] [38] Although the present invention has been described in conjunction with some exemplary embodiments, it will be apparent to one skilled in the art that the present invention may be modified and varied in various forms without departing from the technical spirit of the present invention. It is obvious that all modifications or variations or both fall within the scope of the appended claims.
    [39] [39] The above features and other advantages of the present invention will be better understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
    [40] [40] Fig. 1 is a diagram showing the construction of a conventional SPR sensor for biomaterial analysis;
    [41] [41] Fig. 2 is a graph showing a change in the bond concentration in a process of samples bound to and disassociated from a thin metal layer;
    [42] [42] Fig. 3 is a graph showing the measurement results of an ellipsometric constant Lp using the conventional SPR sensor;
    [43] [43] Figs. 4 to 6 are diagrams illustrating a conventional problem in which the binding and disassociation kinetics inherent in the samples appear in a process in which the samples bind and disassociate, and a change in the refractive index resulting from a buffer solution is mixed together;
    [44] [44] Fig. 7 is a schematic diagram showing the construction of a device for quantifying the binding and disassociation kinetics of molecular interaction according to an embodiment of the present invention;
    [45] [45] Fig. 8 is a perspective view showing an example of a multichannel structure of microflow paths according to the present invention;
    [46] [46] Fig. 9 is an exploded view of the multichannel structure of microflow paths;
    [47] [47] Fig. 10 is a perspective view showing another example of the multipath structure of microflow paths according to the present invention;
    [48] [48] Fig. 11 is an exploded view showing an example of a single channel structure of microflow paths according to the present invention;
    [49] [49] Fig. 12 is a fate diagram illustrating a method for quantifying the binding and disassociation kinetics of molecular interaction according to the present invention;
    [50] [50] Fig. 13 is a graph showing a change of the ellipsometric constants Lp and A according to a change in the refractive index of a buffer solution in cases where a thin dielectric layer is formed on a silicon oxide layer; 10 15 20 25 30 35 10
    [51] [51] Fig. 14 is a graph showing a change in the ellipsometric constants Lp and A according to a change in the thickness of the bonding layer of samples in cases where a thin dielectric layer is formed on a silicon oxide layer;
    [52] [52] Fig. 15 is a graph showing a change in the ellipsometric constants w and A according to a change in the thickness of the bonding layer of samples in cases where a substrate is made of a glass material; and
    [53] [53] Fig. 16 is a graph showing a change in the ellipsometric constant Lp according to a change in the thickness of the bonding layer of samples in cases where a substrate is made of silicon (Si).
    [54] [54]
    [55] [55] <description of reference numerals for principal elements in the drawings>
    [56] [56] 100, 100 ': the structure with microflow paths 110: substrate
    [57] [57] 112: trace unit 120: substrate
    [58] [58] 130: thin dielectric layer 140: envelope unit
    [59] [59] 132: self-assembled monolayers 142: fancy windows
    [60] [60] 144: reflection window 146: barrier ribs
    [61] [61] 150: microflow paths 152: inflow paths
    [62] [62] 154: outflow paths 160: bonding layer
    [63] [63] 200: provincial spraying unit 210: buffer solution
    [64] [64] 300: polarization generating unit
    [65] [65] 310: light source 320: polarizer
    [66] [66] 330: collimator lens
    [67] [67] 350: first compensator 410: analyzer
    [68] [68] 400: polarization detection unit
    [69] [69] 420: photodetector 430: operating processor
    [70] [70] 440: second compensator 450: spectroscope Embodiments of the invention
    [71] [71] Some embodiments of the present invention are described in detail below with reference to the accompanying drawings. The same reference numeral indicates the same element.
    [72] [72]
    [73] [73] [Constructions of a device for quantifying the binding and disassociation kinetics of molecular interaction]
    [74] [74] First, the construction of the device for quantifying the binding and dissociation kinetics of molecular interaction according to an embodiment of the present invention is described with reference to the accompanying drawings. 10 15 20 25 30 35 ll
    [75] [75] Fig. 7 is a schematic diagram showing the construction of a device for quantifying the binding and disassociation kinetics of molecular interaction according to an embodiment of the present invention. As shown in fig. 7, the device for quantifying the binding and disassociation kinetics of molecular interaction according to the invention comprises the embodiment of the present invention mainly a structure 100 of microflow paths and a sample spray unit 200, which provides an environment of microflow paths with immersion in liquid, and an optical system, comprising a polarization generating unit 300 which provides incident light and a polarization detecting unit 400 which detects a change in the polarization of reflected light.
    [76] [76] The present invention is for measuring the binding and disassociation kinetics of biomaterials, including small molecules, using an ellipsometry and a reflectometry. In the device according to the invention, in the provincial spraying unit 200, a buffer solution 210 comprising samples (not shown) of biomaterial is sprayed into the structure 100 of microflow paths. Here, the structure 100 of microfluidic paths may have a microfluidic path 150 formed by a multi-channel or a single channel, as described below.
    [77] [77] Fig. 8 is a perspective view showing an example of a multichannel structure of microflow paths according to the present invention, and Fig. 9 is an exploded view of the multichannel structure of microflow paths. As shown in Figs. 8 and 9, the structure 100 of microfluidic paths comprises a substrate 110, a substrate 120, a thin dielectric layer 130 and an envelope unit 140. The structure 100 of microfluidic paths is designed to have a plurality of microfluidic paths 150 in the form of the multichannel .
    [78] [78] The substrate 110 has a square flat shape, as shown in Fig. 9, and has a longitudinal groove unit 112 formed. The substrate 120 and the thin dielectric layer 130 are formed in the track unit 112. Further, the inflow paths 152 and the outflow paths 154 of the microflow paths 150 are formed on one side and the other on the base of the track unit 112. Here, the track unit 112, the inflow paths 152 and the outflow paths 154 are formed using semiconductor etching techniques or by exposure techniques.
    [79] [79] The substrate 120 has a square flat shape and is formed in the groove unit 112 by the substrate 110. According to the present invention, the substrate 120 is made of silicon (Si) which has a complex refractive index of about 4.1285 + i0.0412 at 532 nm and provides stable physical properties with low costs. However, the substrate 120 may be made of a semiconductor or a dielectric material other than silicon (Si).
    [80] [80] The thin dielectric layer 130 serves to have samples (not shown) of biomaterials with small molecules bound thereto and disassociated therefrom and to reflect incident light. The thin dielectric layer 130 is formed on the substrate 120, as shown in Fig. 9.
    [81] [81] As shown in Figs. 5 to 6b, the casing unit 140 is provided with an incident window 142 and a reflection window 144 provided on one and the other side of the substrate 110, respectively. Here, the incident window 142 and the reflection window 144 are formed in a curved shell shape, which has a predetermined curvature so that the incident light and the reflected light can incident vertically on the incident window 142 and the reflection window 144. As shown in Fig. 9, the envelope unit 140 is further provided with a plurality of barrier ribs 146 to form the microflow paths 150 of a microscale. Only the incident window 142 and the reflection window 144 of the casing unit 140 may be made of a permeable material, such as glass or transparent synthetic resin, but it is preferable that to facilitate manufacture, the entire structure of the casing unit 140, including the casement window 142, the reflection window 144 and the barrier ribs 146 be integrally formed using a casting method. On the other hand, a synthetic resin may include, for example, acrylic acid resin such as polymethyl methacrylate (PMMA). Silicon (Si) -based materials, such as silicon phosphate polymer (PDMS) and polydimethylsiloxane, can also be used as the synthetic resin material.
    [82] [82] The microflow path 150 is a passageway into which the buffer solution 210, including the samples, flows and from which the buffer solution 210, including the samples, is emptied. A plurality of microflow paths 150 are formed. Ie. since each space between the barrier ribs 146 of the envelope assembly 140 communicates with the inflow path 142 and the outflow path 154, which are formed in the substrate 110 as described above, the plurality of microflow paths 150 are formed in the structure 100 of microflow paths. Here, the width of the microflow paths 150 is on a micro scale of 1 mm or less.
    [83] [83] Fig. 10 is a perspective view showing another example of the multichannel structure of microflow paths according to the present invention. As shown in Fig. 10, in a multichannel structure 100 'of microflow paths, the incident window 142' and the reflection window 144 'of an envelope unit 140' may have a flat sheet shape. In such a case, the polarization generating unit 300 and the polarizing detecting unit 400 have fi g. 7 incident light and reflected light incident on the incident window 142 'and the reflection window 144', respectively, at an almost vertical angle in a magnitude so that the polarization state of each of the incident light and the reflected light does not change much or is fixed at the incident the light and the reflected light in respective positions where the incident light and the reflected light are vertically incident on the incident window 142 'and the reflection window 144', respectively.
    [84] [84] Fig. 11 is an exploded perspective view of an example of a single channel structure of microfluidic paths according to the present invention. As shown in Fig. 11, a structure 100 "of single channel microflow paths includes a microflow path 150". Ie. the structure 100 "of microflow paths includes a pair of barrier ribs 146" formed at both ends of an envelope assembly 140 "and an inflow path 152" and an outflow path 154 "formed in a substrate 110, thereby forming the microflow path 150" of a single channel. Furthermore, a plurality of different self-assembling monolayers (SAM) 132 are formed on a thin dielectric layer 130. The self-assembling monolayer 132 is formed of a monomer which is composed of a main group and an end group and is voluntarily arranged by a chemical bonding method of molecules. Here, each of the self-assembled monolayers 132 may have different interface characteristics through chemical transformation of the functional group in the end group of the self-assembled monolayer 132. Ie. each of the self-assembled monolayers 132 has a sensor structure with different degrees of binding and dissociation from a sample, and the self-assembled monolayer 132 may simultaneously have varying binding and disassociation kinetics for biomaterials.
    [85] [85] The sample spray unit 200, as shown in Fig. 7, injects the buffer solution 210, including samples (not shown) made of small molecule biomaterials, into the inflow path 152 of the microflow paths 150. The sample spray unit 200 includes a valve device (not shown) which is performed dissolving the samples in the buffer solution 210 at a predetermined concentration and injecting the buffer solution 210 into the microfluidic pathways 150 or closing the injection of the samples. Here, the sample spray unit 200 can inject the buffer solution 210 into the microflow paths 150 in each channel in the state in which the samples have different concentrations or have an intermediate time. On the other hand, when the buffer solution 210 is injected into the microfluidic paths 150, some of the samples (not shown) may be bonded to the thin dielectric layer 130, thereby forming a bonding layer 160 of a predetermined thickness. Here, the bonding layer 160 may be a multilayer layer, consisting of the self-assembling monolayer 132 suitable for the bonding characteristics of various biomaterials, an oxidizing material, and various biomaterials comprising molecules bound to the fixing material.
    [86] [86] The polarization generating unit 300, as shown in Fig. 7, functions to radiate incident light, polarized through the incident window 142 of the structure 100 by microfluidic paths to the bonding layer 160. The polarizing generating unit 300 may include a light source 210 and a polarizer 320 as important elements and may further comprise a collimator lens 330, a focusing lens 340 or a first compensator 350. Here the polarizer 320 and the first compensator 350 may be rotatably designed or may additionally comprise other polarization modulating means. On the other hand, the polarized incident light may have polarized components of the p-wave and s-wave type, and light closest to the p-wave may fall on the bonding layer 160 to increase the signal-to-noise ratio. In the present invention, incident light is to be emitted at an angle of incidence 6 which satisfies a non-reflective state of p-waves. In an ellipsometric equation, a complex factor ratio can be represented by a ratio between the reflection factor Rp for p-waves and the reflection factor Rs for s-waves (ie p = Rp / Rs). The state of non-reflecting p-waves refers to a state in which the reflection factor Rp for p-waves has a value close to 0. The state of non-reflective p-waves is similar to the surface plasmon resonance state of the conventional SPR sensor and is a state in which the measurement sensitivity of the present invention is a maximum.
    [87] [87] The light source 310 emits monochromatic light that has the same wavelength band as infrared rays, visible rays or ultraviolet rays or rays of white light. Various lamps, a light emitting diode (LED), a laser or a laser diode (LD) may be the light source 310. Here, the light source 310 may comprise a structure capable of varying the wavelength according to the structure of an optical system. On the other hand, the magnitude of an optical signal in the reflected light may be relatively small near the above-described state of non-reflective p-waves. In this case, the signal-to-noise ratio can be increased by irradiating light with a high proportion of light using a laser or a laser diode (LD), in order to achieve a highly sensitive measurement.
    [88] [88] The polarizer 320 includes a polarizing disk and polarizes the light radiating from the light source 310. Here, the components of the polarized light include p-waves parallel to the incident surface and s-waves that are vertical to the incident surface.
    [89] [89] The collimator lens 330 receives the light from the light source 310 and provides parallel light to the polarizer 320. Furthermore, the focusing lens 340 can increase the amount of incident light by converging the parallel light passing through the polarizer 320. Furthermore, the first compensator 350 acts to phase delay the polarized ones. the components of the incident light. 10 15 20 25 30 35 15
    [90] [90] The polarization detection unit 400 functions, as shown in Fig. 7, to receive light reflected by the binding layer 160 through the reflection window 144 and to detect a change in the polarization state of the reflected light. The polarization detecting unit 400 comprises an analyzer 410, a photodetector 420 and an operating processor 430 (ie main elements) and may further comprise a second compensator 440 and a spectroscope 450. Here the analyzer 410 corresponds to the polarizer 320 and comprises a polarizing disk. The analyzer 410 can control the degree of polarization of reflected light or the direction of a polarizing surface by polarizing the reflected light again. Furthermore, the analyzer 410 may be rotatably constructed according to the structure of an optical system, or it may further comprise polarization modulating means capable of performing functions such as phase change or quenching of polarized components.
    [91] [91] The photodetector 420 functions to obtain optical data by detecting polarized reflected light and to convert optical data into an electrical signal. Here, optical data includes information about a change in the polarization state of the reflected light. A CCD type semiconductor system, a photomultiplier (PMT) or a silicon photodiode can be used as the photodetector 420.
    [92] [92] The operation processor 430 functions to induce quantified values by obtaining the electrical signal from the photodetector 420. The operation processor 430 has a predetermined interpretation program using a reflectometry and ellipsometry enclosed therein.
    [93] [93] The second compensator 440 functions to control the polarized components of the reflected light by phase delay. The second compensator 440 may be rotatable, or it may additionally include other polarization modulating means.
    [94] [94] The spectroscope 450 can be used in cases where the light source 310 is a white light source.
    [95] [95]
    [96] [96] [Method for quantifying the binding and disassociation kinetics of molecular interaction] 10 15 20 25 30 35 16
    [97] [97] The procedure and principles for quantifying the binding and dissociation kinetics of molecular interaction are described below.
    [98] [98] Fig. 12 is a fate diagram illustrating the method for quantifying the binding and disassociation kinetics of molecular interaction according to the present invention. As shown in fi g. 12, the quantification process of the present invention undergoes a first step S100 to a fifth step S500.
    [99] [99] In the first step S100, as in Fig. 7, the sample spray unit 200 dissolves the samples (not shown) of biomaterials, including small molecules, in the buffer solution 210 and injects them into the microfluidic paths 150 of the microflow path structure 100. Here, the sample spray unit 200 can inject the buffer solution 210, including samples of different concentrations, into respective microflow paths 150 of multiple channels. Further, the sample spraying unit 200 may inject the buffer solution 210 at an interval of respective microfluidic walls 150. Further, the sample spraying unit 200 may inject the buffer solution into some of the microfluidic paths 150 and then not use the remaining microflow paths 150.
    [100] [100] In the second step S200, the samples (not shown) of biomaterial are bonded to the thin dielectric layer 130, thus forming the bonding layer 160. Unlike the above, the samples can be bonded to the plurality of different self-assembled monolayers 132 which are formed in the structure 100 "by microflow paths of a single channel shown in Fig. 11, thus forming the bonding layer 160 having different bonding characteristics.
    [101] [101] In the third stage S300, predetermined light emitted from the light source 310 is polarized by the polarizer 320 and then incident on the bonding layer 160 through the incident window 142 of the structure 100 by microflow paths. Here, the polarized incident light has polarized components of p-waves and s-waves. On the other hand, the incident light must have an angle of incidence 9 which satisfies a non-reflective state for p-waves.
    [102] [102] In the third stage S400, the reflected light reflected by the bonding layer 160 falls on the polarization detection unit 400 through the reflection window 144 of the structure 100 of microfluidic paths. Here, the reflected light is in an elliptical polarized state.
    [103] [103] In the fifth stage S500, the polarization detection unit 400 detects the polarized state of the reflected light. in particular, the analyzer 410 first receives the elliptically polarized reflected light from the bonding layer 160 and transmits only light according to a polarization characteristic.
    [104] [104] Thereafter, the photodetector 420 obtains predetermined optical data by detecting a change in the polarized components of the reflected light, converts this optical data into an electrical dignal and transmitting the electrical signal to the operating processor.
    [105] [105] Thereafter, the operating processor 430, which has a program using a reflectometry or ellipsometry contained therein, induces quantified values such as the binding concentration, binding and disassociation constants and refractive index of the samples by extracting and interpreting the optical data converted into electrical signal. . Here, in the present invention, the operating processor 430 induces the quantized values by finding the amplitude ratio Lp and the phase difference A in an ellipsometry. The values of the phase difference A have an excellent sensitivity which is 10 times greater than the value of the amplitude ratio Lp, except for angles very close to the non-reflecting angle for p-waves. The measurement sensitivity can be improved by measuring the value of the phase difference A. However, at the non-reflecting angle of p-waves, there is almost no change in the phase difference A and the sensitivity of the values of the amplitude ratio Lp is much improved. In particular, a change in the value of the amplitude ratio Lp at the non-reflective angle of p-waves is advantageous for quantitative measurement because it has a linear change in response to only a change in the thickness or refractive index of a bonding material regardless of the thin dielectric layer which is a substrate material.
    [106] [106]
    [107] [107] [Examples of experiments]
    [108] [108] Fig. 13 is a diagram showing a change in the ellipsometric constants and consequently in the refractive index of the buffer solution in the case where the round dielectric layer is formed on a silicon oxide layer. l fi g. In Fig. 13, the light source 310 had a wavelength of 532 nm and a silicon oxide layer of 2 nm in thickness was used as the thin dielectric layer 130. In Fig. 13 it can be seen that an angle of incidence corresponding to a non-reflective state of the p-waves is about 72 ° at which the values of the ellipsometric constants Lp and A change abruptly. It can also be seen that in cases where the bonding layer 160 is not formed (0 nm), there is almost no change in the values of the ellipsometric constants Lp and A according to a change (1, 333, 1,334) in the refractive index of the buffer solution 210. This means that only the binding and disassociation kinetics built into the samples can be measured because the thin dielectric layer 130 which provides a stable light characteristic is used.
    [109] Furthermore, in the case where the refractive index of the buffer solution 210 is regular (1,333) and the thickness of the bonding layer 160 changes from 0 nm to 1 nm, a change in the value of the amplitude ratio Lp is sensitive at the non-reflective angle of p-waves, and sensitivity the ten of the phase difference A is excellent except at angles very close to the non-reflecting angle for p-waves. 10 15 20 25 30 18
    [110] [110] Fig. 14 is a diagram showing a change in the ellipsometric constants Lp and A according to a change in the thickness of the bonding layer in samples in cases where the thin dielectric layer is formed on a silicon oxide layer. Fig. 14 shows a case in which the refractive index of the buffer solution 210 is regular (1, 333) and the thickness of the bonding layer 160 is 0 nm to 3 nm. I fi g. 14, it can be seen that there is a change in the value of the ellipsoometric constants Lp and A at an angle of incidence of approximately 72 ° corresponding to the non-reflective state of p-waves. I fi g. 14 it can be seen that at the non-reflecting angle of p-waves a change in the value of the amplitude ratio Lp is sensitive and the sensitivity of the phase difference A is excellent except at angles very close to the non-reflecting angle of p-waves.
    [111] [111] Fig. 15 is a graph showing a change in the ellipsometric constants Lp and A according to a change in the thickness of the bonding layer in samples in cases where the substrate 120 is made of a glass material and where the thin dielectric layer is not used (0 nm ). In Fig. 15, the light source 310 had a wavelength of 532 nm and a glass layer (SF 10) was used as the substrate 120. In fi g. It can be seen that an angle of incidence corresponding to a non-reflective state of the p-waves is approximately 52.5 at which the values of the ellipsometric constants Lp and A change suddenly. In the same way as the above experiments, it can be seen that the values of the ellipsometric constants Lp and A change according to a change in the thickness of the bonding layer 160 (1 nm to 4 nm). Furthermore, it can be seen in Fig. 15 that at the non-reflecting angle for p-waves, a change in the value of the amplitude ratio Lp is sensitive and the sensitivity of the phase difference A is excellent except at angles very close to the non-reflecting angle for p-waves.
    [112] [112] Fig. 16 is a diagram showing a change in the ellipsometric constants Lp and A according to a change in the thickness of a silicon oxide layer or an absorbent material in cases where the substrate is made of silicon (Si). In Fig. 16 it can be seen that at the non-reflecting angle of p-waves there is almost no change in the phase difference A and there is a noticeable change in the value of the amplitude ratio Lp. Here it can be seen that a change in the value of the amplitude ratio Lp has a linear change in response to a change in the thickness or refractive index of a thin layer bonded to a substrate material. If the wavelength of the incident light and the refractive index of a medium are known, quantitative measurement is possible based on the values of the amplitude ratio Lp. Accordingly, if the device and method for quantifying the binding and disassociation kinetics of molecular interaction of the present invention are used, a biosensor capable of quantitatively analyzing only one change according to only one binding characteristic can be used unlike the SPR sensor. which is sensitive to a change in the surrounding environment.
    权利要求:
    Claims (23)
    [1]
    An apparatus for quantifying the binding and disassociation kinetics of molecular interaction, comprising: a structure (100) for microfluidic pathways, comprising a substrate (110), a substrate (120) formed on the substrate (110) and made of a semiconductor or of a dielectric material, a thin dielectric layer (130) formed on the substrate (120), an enveloping unit (140) which is formed so as to have an incident window (142) and a reflection window (144) arranged on one and on the other side and are arranged on the substrate (110), and microflow paths (150) formed in the substrate (110) and between the substrate (110) and the envelope unit (140); a sample spray unit (200) for forming a bonding layer (160) of samples on the thin dielectric layer (130) by injecting a buffer solution (210), comprising the samples of a biomaterial into the microfluidic pathways (150); a polarizing generating unit (300) for irradiating incident light, polarized through the incident window (142), to the bonding layer (160) at an angle of incidence 9 satisfying a state of non-reflective p-wave; and a polarization detection unit (400) for detecting a change in the polarization of reflected light in the bonding layer (160) which is incident through the reflection window (144).
    [2]
    The device of claim 1, wherein the thin dielectric layer (130) comprises a semiconductor oxide layer or a glass layer made of a transparent material.
    [3]
    The device of claim 2, wherein the thin dielectric layer (130) has a thickness of 0 to 1000 nm.
    [4]
    The device of claim 1, wherein the structure (100) of microflow paths comprises: a plurality of inflow paths (152) and a plurality of outflow paths (154) formed on one and the other side of the substrate (110), respectively, and the microflow paths ( 150) of the plurality of channels are configured to have a plurality of barrier ribs (146) formed on an inside of the envelope assembly (140) and to connect the inlet paths (152) and the outflow paths (154), respectively.
    [5]
    The apparatus of claim 1, wherein the structure (100) of microfluidic paths forms the microfluidic path (150) for a single channel, and a plurality of different self-assembled monolayers (132) to which the samples are bonded are further formed on the thin dielectric layer (130). ).
    [6]
    The device of claim 4, wherein: each of the incident window (142) and the reflection window (144) of the envelope unit (140) has a curved shell shape with a predetermined curvature, and the incident light and the reflecting light the light is incident on the incident window (142) and the reflection window (144), respectively, at a vertical angle or at an almost vertical angle with a magnitude such that a polarized state of each of the incident light and the reflecting light does not change so much.
    [7]
    The device of claim 4, wherein: each of the incident window (142) and the reflection window (144) of the envelope assembly (140) has a planar sheet shape, and the incident light and the reflecting light incident on the incident window (142) and the reflection window (142), respectively. 144), at a vertical angle or at an almost vertical angle with a magnitude such that a polarized state of each of the incident light and the reflecting light does not change so much.
    [8]
    The device of claim 4, wherein the envelope assembly (140) is integrally made of glass or a transparent synthetic resin material.
    [9]
    The device of claim 1, wherein the bonding layer (160) is a multilayer layer, comprising a self-assembled monolayer (132) suitable for bonding properties of different biomaterials, an oxidizing material, and various biomaterials including molecules bound to the fixing material.
    [10]
    The apparatus of claim 1, wherein the polarization generating unit (300) comprises: a light source (310) for radiating predetermined light, and a polarizer (320) for polarizing the radiated light.
    [11]
    11.. The device of claim 10, wherein the light source (310) emits monochromatic light or white light.
    [12]
    The device of claim 10, wherein the light source (310) is a laser or a laser diode having a wavelength variable structure.
    [13]
    The apparatus of claim 10, wherein the polarization generating unit (300) comprises at least one of: a collimator lens (330) for providing parallel light to the polarizer (320), a focusing lens (340) for increasing an amount of the incident light by converging the parallel light passing through the polarizer (320), and a first compensator (350) for phase delay of polarized components of the incident light. 10 15 20 25 30 35 22
    [14]
    Device according to claim 13, wherein the polarizer (320) and the first compensator (350) are rotatably designed or additionally equipped with other means for polarization modulation.
    [15]
    The apparatus of claim 1, wherein the polarization detection unit (400) comprises: an analyzer 410 configured to polarize the reflected light, a photodetector (420) configured to obtain predetermined data by detecting the polarized reflected light, and a operating processor (430) electrically connected to the photodetector (420) and configured to induce quantified values based on optical data.
    [16]
    The device of claim 15, wherein the photodetector (420) comprises one of a CCD-Iyp semiconductor system, a photomultiplier and a silicon photodiode.
    [17]
    The apparatus of claim 15, wherein the operating processor (430) induces the quantified values, including a binding concentration, a binding constant, and a disassociation constant for the samples, by finding an ellipsometric constant tp or A.
    [18]
    The apparatus of claim 15, wherein the polarization detector unit (400) further comprises at least one of: a second compensator (440) for phase delay of polarized components of the reflected light, and a spectroscope (450) for making a spectrum of the reflected light.
    [19]
    Device according to claim 18, wherein the analyzer (410) and the second compensator (440) are rotatably designed or additionally equipped with other means for polarization modulation.
    [20]
    A method for quantifying the binding and disassociation kinetics of molecular interaction, the method comprising: a first step S100 of a sample spray unit (200) injecting a buffer solution (210), including samples of small molecular biomaterials, into microfluidic pathways ( 150) of a structure (100) of microfluidic pathways; a second step S200 in which samples are bonded to a thin dielectric layer (130) of the microflow path structure (100), so as to form a bonding layer (160), a third step S300 of a polarization generating unit (300) which polarizes predetermined light and makes it polarized the light so that it impinges on the bonding layer (160) with an angle of incidence on to satisfy a non-reflective state of p-waves through an incident window (142) of the structure (100) of microwave current paths; a fourth step S400 wherein reflected light of the bonding layer (160) is incident on a polarization detection unit (400) through a reflection window (144) of the structure (100) of microflow paths; and a fifth step S500 wherein the polarization detecting unit (400) detects a polarization state of the reflected light using an ellipsometry or a reflectometry.
    [21]
    The method of claim 20, wherein in the first step S100, the buffer solution 210 including the samples of different concentrations is injected into the respective microflow paths (150) of the structure (100) of microflow paths comprising multiple channels.
    [22]
    The method of claim 20, wherein in the second step S200, the samples are bonded to a plurality of different self-assembled monolayers (132) formed on the thin dielectric layer (130), so as to form the various bonding layers (160). .
    [23]
    The method of claim 20, wherein the fifth step S500 comprises: a step of an analyzer (410) polarizing the reflected light, a step of a photodetector (420) obtaining predetermined optical data by detecting the polarized reflected light, and a step in which an operating processor (430) induces quantified values, including a binding concentration, a binding constant and a disassociation constant of the samples, by finding an ellipsometric constant qi or A of the ellipsometry based on these optical data.
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    US20120295357A1|2012-11-22|
    CN102713609B|2014-10-22|
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    KR20110056720A|2011-05-31|
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