Surface-enhanced Raman scattering spectroscopic structure, its manufacturing method and diagnostic method using the same

Abstract

The present invention relates to a surface-enhanced Raman scattering spectroscopy structure, a method for manufacturing the same, and a diagnostic method using the same.The surface-enhanced Raman scattering spectroscopy structure, the method for manufacturing the same, and the diagnostic method using the same according to the present invention can provide a surface-enhanced Raman scattering spectroscopy structure and a method for manufacturing the same that can be used even when there are no biomarkers with excellent diagnostic performance among blood indicators, as with intractable cancers and intractable diseases such as pancreatic cancer.Furthermore, a diagnostic method and a diagnostic system can be provided that use surface-enhanced Raman scattering spectroscopy in the surface-enhanced Raman scattering spectroscopy structure.

Description

[Technical Field]

[0001] The present invention relates to a surface-enhanced Raman scattering spectroscopic structure, a method for producing the same, and a diagnostic method using the same. [Background technology]

[0002] Surface-enhanced Raman scattering (SERS) spectroscopy is a method designed to complement Raman scattering spectroscopy, which has a weak signal and poor reproducibility. The Raman scattering intensity of molecules adsorbed on the surface of metal nanostructures such as gold and silver increases sharply by 10 6 ~10 8 This is a spectroscopic method that uses the phenomenon of light intensity being enhanced by more than 2 times.

[0003] Surface-enhanced Raman scattering (SERS) spectroscopy is an ultra-sensitive technique that can obtain a large amount of information in a single measurement and can directly measure a single molecule. It can directly measure information about the vibrational state or molecular structure of a molecule, and is recognized as a powerful analytical method for chemical, biological, and biochemical analysis.

[0004] Recently, surface-enhanced Raman scattering spectroscopy has attracted attention as a sophisticated method for obtaining comprehensive information about biomolecules from bioanalytical samples. However, previously proposed methods for detecting biomolecules using surface-enhanced Raman scattering spectroscopy require specific binding, and there are no blood biomarkers with excellent diagnostic performance for intractable cancers and diseases such as pancreatic cancer, making screening tests and early diagnosis difficult.

[0005] Therefore, there is a current need for a diagnostic method and system using surface-enhanced Raman scattering spectroscopy that can be used even when there are no biomarkers with excellent diagnostic performance among biological indicators, such as in the case of intractable cancers and intractable diseases such as pancreatic cancer.

[0006] On the other hand, the matters described as background art are intended to deepen understanding of the background of the present invention and should not be construed as an admission that they constitute prior art already known to those having ordinary skill in the art. Summary of the Invention [Problem to be solved by the invention]

[0007] The technical problem that the present invention aims to achieve is to provide a surface-enhanced Raman scattering spectroscopy structure and a method for manufacturing the same that can be used even when there are no biomarkers with excellent diagnostic performance among blood indicators, as in the case of intractable cancers and intractable diseases such as pancreatic cancer.

[0008] The technical problem to be achieved by the present invention is to provide a method and system for diagnosing diseases using surface-enhanced Raman scattering spectroscopy that can be used even when there is no biomarker with excellent diagnostic performance among biological indicators.

[0009] Another technical problem that the present invention aims to achieve is to provide a diagnostic method and diagnostic system using surface-enhanced Raman scattering spectroscopy that is highly reproducible and convenient for distribution and storage.

[0010] The technical problems that the present invention aims to achieve are not limited to the above-mentioned technical problems, and other technical problems not mentioned will be clearly understood by those having ordinary skill in the art to which the present invention pertains from the following description. [Means for solving the problem]

[0011] In order to achieve the above technical objective, one embodiment of the present invention provides a surface-enhanced Raman scattering spectroscopy structure, comprising: a silica shell layer having an internal storage space; and nanoparticles having a plasmonic metal, the nanoparticles being disposed in a region of the internal storage space of the silica shell layer.

[0012] In order to achieve the above technical objective, another embodiment of the present invention provides a method for manufacturing a structure for surface-enhanced Raman scattering spectroscopy, comprising the steps of preparing a solution in which nanoparticles are dispersed, and forming a silica shell layer surrounding the nanoparticles dispersed in the solution.

[0013] In order to achieve the above technical objective, one embodiment of the present invention provides a method for diagnosing diseases using surface-enhanced Raman scattering spectroscopy, comprising the steps of: acquiring a first surface-enhanced Raman scattering spectroscopic signal from a biological solution extracted from a patient; irradiating light onto a diagnostic solution in which metallic nanostructures having biomolecular substances in one region thereof are dispersed, and acquiring a second surface-enhanced Raman scattering spectroscopic signal in the one region of the metallic nanostructures; and comparing the first surface-enhanced Raman scattering spectroscopic signal with the second surface-enhanced Raman scattering spectroscopic signal to identify a disease of the patient.

[0014] In order to solve the above technical problems, another embodiment of the present invention provides a disease diagnosis system using surface-enhanced Raman scattering spectroscopy, comprising: a container portion in which a diagnostic solution is placed; an irradiation portion that irradiates light onto the diagnostic solution placed in the container portion to generate a surface-enhanced Raman scattering spectroscopy signal in a region of a metal nanostructure contained in the diagnostic solution; and a diagnostic portion that analyzes the generated surface-enhanced Raman scattering spectroscopy signal. [Effects of the Invention]

[0015] According to one embodiment of the present invention, it is possible to provide a surface-enhanced Raman scattering spectroscopy structure and a method for manufacturing the same that can provide a surface-enhanced Raman scattering spectroscopy signal nonspecifically to a biomolecular substance.

[0016] Furthermore, according to one embodiment of the present invention, it is possible to provide a surface-enhanced Raman scattering spectroscopy structure and a method for manufacturing the same that can be used even when there are no biomarkers with excellent diagnostic performance among blood indicators, as with intractable cancers and intractable diseases such as pancreatic cancer.

[0017] According to one embodiment of the present invention, it is possible to provide a diagnostic method and a diagnostic system using surface-enhanced Raman scattering spectroscopy that can be used even when there is no biomarker with excellent diagnostic performance among biological indicators.

[0018] Furthermore, according to one embodiment of the present invention, it is possible to provide a diagnostic method and a diagnostic system using surface-enhanced Raman scattering spectroscopy that are highly reproducible and convenient for distribution and storage.

[0019] The effects of the present invention are not limited to the effects described above, but should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description of the present invention or the claims. [Brief explanation of the drawings]

[0020] 1A to 1E are conceptual diagrams showing a surface-enhanced Raman scattering spectroscopy structure provided by one embodiment of the present invention. 2A and 2B are conceptual diagrams illustrating a diagnostic solution for surface-enhanced Raman scattering spectroscopy provided by one embodiment. 3A and 3B are a flowchart illustrating a method for fabricating a surface-enhanced Raman scattering spectroscopy structure provided in accordance with one embodiment. 4A and 4B are flowcharts of a diagnostic method using surface-enhanced Raman scattering spectroscopy provided by one embodiment. 5A-5C are block diagrams illustrating a diagnostic system provided in accordance with one embodiment. 6A and 6B are TEM images of a surface-enhanced Raman scattering spectroscopy structure provided in accordance with one embodiment. FIG. 7 shows the results of a Raman scattering experiment when a biological material is present and absent inside a structure according to one embodiment. FIG. 8 is a diagram showing experimental results regarding the difference in Raman spectrum between with and without ethanol pretreatment according to one embodiment. FIG. 9 is a diagram confirming the surface-enhanced Raman scattering spectroscopic signal of a diagnostic solution provided according to one embodiment. BEST MODE FOR CARRYING OUT THE INVENTION

[0021] One embodiment of the present invention can provide a surface-enhanced Raman scattering spectroscopy structure including a silica shell layer having an internal storage space and nanoparticles comprising a plasmonic metal, the nanoparticles being positioned in a region of the internal storage space of the silica shell layer.

[0022] One embodiment of the present invention can provide a surface-enhanced Raman scattering spectroscopy structure, wherein the nanoparticle comprises a core including a first plasmonic metal and a second plasmonic metal shell layer surrounding the core and including a second plasmonic metal, and the second plasmonic metal shell layer has a symmetrical structure with respect to the center of the second plasmonic metal shell layer.

[0023] Moreover, one embodiment of the present invention may be a surface-enhanced Raman scattering spectroscopy structure, wherein the structure includes a biomolecular substance disposed in the accommodation space.

[0024] Furthermore, one embodiment of the present invention may be a surface-enhanced Raman scattering spectroscopy structure, in which the first plasmonic metal and the second plasmonic metal each independently include any one or more selected from the group consisting of Au, Ag, Cu, Al, W, Pt, Ni, and Pd.

[0025] Furthermore, one embodiment of the present invention may be a surface-enhanced Raman scattering spectroscopy structure in which the width of the plasmon resonance peak at the surface of the second plasmonic metal is narrower than the width of the plasmon resonance peak at the surface of the first plasmonic metal.

[0026] Furthermore, one embodiment of the present invention may be a surface-enhanced Raman scattering spectroscopy structure, in which the second plasmonic metal shell layer has a regular polyhedron structure.

[0027] Another embodiment of the present invention can provide a method for manufacturing a structure for surface-enhanced Raman scattering spectroscopy, comprising the steps of preparing a solution in which nanoparticles are dispersed, and forming a silica shell layer surrounding the nanoparticles dispersed in the solution.

[0028] In one embodiment of the present invention, the step of preparing a solution in which the nanoparticles are dispersed includes a step of mixing a first solution containing a first precursor compound including a first plasmonic metal with a second solution containing a second precursor compound including a second plasmonic metal to form a mixed solution, and the nanoparticles include a core containing the first plasmonic metal and a second plasmonic metal shell layer surrounding the core and including the second plasmonic metal, and the second plasmonic metal shell layer has a symmetrical structure with respect to the center of the second plasmonic metal shell layer.

[0029] Furthermore, one embodiment of the present invention may be a method for manufacturing a structure for surface-enhanced Raman scattering spectroscopy, further comprising the step of mixing a coating solution containing a water-soluble polymer compound with the mixed solution.

[0030] Furthermore, one embodiment of the present invention can provide a method for manufacturing a structure for surface-enhanced Raman scattering spectroscopy, wherein the step of forming the silica shell layer includes a step of mixing the mixed solution with a third solution containing a biomolecular material and a fourth solution containing a silica precursor compound, and the silica shell layer is formed so that the nanoparticles and at least a portion of the biomolecular material are arranged together inside.

[0031] Yet another embodiment of the present invention can provide a method for diagnosing a disease using surface-enhanced Raman scattering spectroscopy, comprising the steps of: acquiring a first surface-enhanced Raman scattering spectroscopic signal from a biological solution extracted from a patient; irradiating light onto a diagnostic solution in which a surface-enhanced Raman scattering spectroscopy structure having a biomolecular substance in one region thereof is dispersed, and acquiring a second surface-enhanced Raman scattering spectroscopic signal in the one region of the surface-enhanced Raman scattering spectroscopy structure; and comparing the first surface-enhanced Raman scattering spectroscopic signal with the second surface-enhanced Raman scattering spectroscopic signal to identify a disease of the patient.

[0032] Another embodiment of the present invention may be a disease diagnosis method using surface-enhanced Raman scattering spectroscopy, in which the surface-enhanced Raman scattering structure further includes a silica shell layer having an internal storage space and nanoparticles containing a plasmonic metal, and the nanoparticles and the biomolecular substance are disposed in the internal storage space of the silica shell layer.

[0033] Furthermore, one embodiment of the present invention may be a disease diagnosis method using surface-enhanced Raman scattering spectroscopy, wherein the biomolecular substance includes two or more types of biomolecular substances.

[0034] Furthermore, one embodiment of the present invention may be a disease diagnosis method using surface-enhanced Raman scattering spectroscopy, wherein the diagnostic method further includes a step of creating a database of the first surface-enhanced Raman scattering spectroscopy signals obtained from the biological solution extracted from the patient.

[0035] Furthermore, one embodiment of the present invention may be a disease diagnosis method using surface-enhanced Raman scattering spectroscopy, wherein the diagnostic method further includes the steps of acquiring a surface-enhanced Raman scattering spectroscopic signal for the biomolecular substance and creating a database of information on the surface-enhanced Raman scattering spectroscopic signal for the biomolecular substance.

[0036] Another embodiment of the present invention can provide a disease diagnostic system using surface-enhanced Raman scattering spectroscopy, including a container portion in which a diagnostic solution is placed, an irradiation portion that irradiates the diagnostic solution placed in the container portion with light to generate a surface-enhanced Raman scattering spectroscopy signal in a region of a metal nanostructure contained in the diagnostic solution, and a diagnostic portion that analyzes the generated surface-enhanced Raman scattering spectroscopy signal.

[0037] In one embodiment, the surface-enhanced Raman scattering spectroscopy structure may be a disease diagnostic system using surface-enhanced Raman scattering spectroscopy, further comprising a silica shell layer having an internal storage space and nanoparticles containing a plasmonic metal, wherein the nanoparticles and the biomolecular substance are disposed in the internal storage space of the silica shell layer.

[0038] In one embodiment, the biomolecular substance may be a disease diagnostic system using surface-enhanced Raman scattering spectroscopy, the system including two or more types of biomolecular substances.

[0039] In one embodiment, the diagnostic system may be a disease diagnostic system using surface-enhanced Raman scattering spectroscopy, further including a data storage unit that acquires the surface-enhanced Raman scattering spectroscopy signal and stores spectroscopic information for the surface-enhanced Raman scattering spectroscopy signal. DETAILED DESCRIPTION OF THE INVENTION

[0040] The present invention will be described below with reference to the accompanying drawings. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein. In the drawings, parts that are not relevant to the description are omitted to clearly explain the present invention, and similar parts are designated by similar reference numerals throughout the specification.

[0041] In the drawings, the size of components may be exaggerated or reduced for the sake of convenience of explanation. For example, the size and thickness of each component shown in the drawings may be arbitrarily shown for the sake of convenience of explanation, and the following embodiments are not necessarily limited to those shown.

[0042] Terms such as "first," "second," "A," and "B" may be used to describe various components, but the components should not be limited by these terms. These terms are used only to distinguish one component from another. For example, a first component can be designated a "second component," and similarly, a second component can be designated a "first component," without departing from the scope of the present invention. The term "and / or" includes a combination of multiple listed related items or any of multiple listed related items.

[0043] Throughout this specification, when a part is said to be "connected (connected, contacted, coupled)" to another part, this includes not only when it is "directly connected" but also when it is "indirectly connected" via another member therebetween.

[0044] Furthermore, when a part is said to "comprise" certain elements, this means that it may further comprise other elements, rather than excluding other elements, unless specifically stated to the contrary.

[0045] The terms used in this specification are merely used to describe specific embodiments and are not intended to limit the present invention. The singular expressions include the plural expressions unless the context clearly indicates otherwise.

[0046] As used herein, terms such as "comprise" or "have" are intended to specify the presence of features, numbers, steps, operations, components, parts, or combinations thereof described herein, and should be understood as not precluding the possible presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0047] When something is referred to as "on" another object, it does not only mean directly on top of the other object, but also includes cases where there is an intervening object.

[0048] Previously proposed methods for detecting biomolecules using surface-enhanced Raman scattering spectroscopy involve the formation of specific bonds between biomolecules and metal nanoparticles, resulting in the formation of surface-enhanced Raman scattering signals at these sites. This has made it difficult to use surface-enhanced Raman scattering spectroscopy for diseases such as pancreatic cancer, for which there are no biomarkers with excellent diagnostic capabilities.

[0049] 1A to 1E are conceptual diagrams showing a surface-enhanced Raman scattering spectroscopy structure provided by one embodiment of the present invention.

[0050] Referring to FIG. 1A, in order to solve the above-mentioned technical problems, one embodiment of the present invention provides a structure 10 for surface-enhanced Raman scattering spectroscopy (hereinafter referred to as "structure") including nanoparticles 11 and a silica shell layer 12, a composition for surface-enhanced Raman scattering spectroscopy in which the structure 10 is dispersed, and a method for producing the same.

[0051] In addition, as an optional embodiment, the interior of the silica shell layer 12 may contain a biomolecular substance B, which will be described later, and the structure may be used to obtain surface-enhanced Raman scattering spectroscopy signals for a considerable number of biomolecular substances B non-specifically arranged within the structure 10 without excluding a specific biomolecular substance B.

[0052] Furthermore, by using such structures 10 and a composition for surface-enhanced Raman scattering spectroscopy in which these structures 10 are dispersed to create a database of surface-enhanced Raman scattering signals, it is possible to provide a diagnostic kit with excellent diagnostic performance even for diseases for which no biomarker with excellent spectroscopic performance exists.

[0053] The structure 10 will now be described.

[0054] In one embodiment, the nanoparticles 11 can include a plasmonic metal. A surface-enhanced Raman scattering spectroscopic signal can be obtained when molecules or particles are present near the surface of the plasmonic metal, as the Raman scattering signal is enhanced through the plasmon phenomenon at the local surface.

[0055] As used herein, "plasmonic metal" can refer to a metal that undergoes stimulation in a magnetic field, such as Au, Ag, Cu, Al, W, Pt, Ni, and Pd.

[0056] In one embodiment, nanoparticle 11 can include a core 111 containing a first plasmonic metal and a second plasmonic metal shell layer 112 surrounding core 111 and comprising a second plasmonic metal. By providing nanoparticle 11 with a core-shell structure such as the above, nanoparticle 11 can be provided with properties of both the first plasmonic metal and the second plasmonic metal.

[0057] In one embodiment, the second plasmonic metal shell layer 112 may have a symmetric structure with respect to the center M of the second plasmonic metal shell layer 112. By having the second plasmonic metal shell layer 112 have a symmetric structure surrounding the core 111 as in the above structure, the surface area between the nanoparticle 11 and the biomolecular substance B can be increased, and the surface-enhanced Raman scattering spectroscopy signal can be maximized.

[0058] In one embodiment, the second plasmonic metal shell layer 112 can have a regular polyhedron structure, which can include, for example, a cube, a regular octahedron, a regular dodecahedron, and / or a regular icosahedron.

[0059] In one embodiment, the core 111 includes a first plasmonic metal, and the first plasmonic metal should be understood to be within the scope of the present invention as long as it is a metal that can provide a surface-enhanced Raman scattering spectroscopic signal through a plasmon phenomenon at the surface, such as, but not limited to, Au, Ag, Cu, Al, W, Pt, Ni, and Pd.

[0060] In one embodiment, the core 111 has an average particle size (D 50 ) can be 50 nm or less. As another example, the thickness can be set to 0 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 0 to 45, 5 to 45, 10 to 45, 15 to 45, 20 to 45, 25 to 45, 30 to 45, 35 to 45, 40 to 45, 0 to 40, 5 to 40, 10 to 40, 15 to 4 It may be 0, 20-40, 25-40, 30-40, 35-40, 0-35, 5-35, 10-35, 15-35, 20-35, 25-35, 30-35, 0-30, 5-30, 10-30, 15-30, 20-30, 25-30, 0-25, 5-25, 10-25, 15-25, or 20-25.

[0061] When the structure 10 has the above average particle size, it can provide an excellent Raman scattering effect when it is placed in a dispersion liquid 20 described later.

[0062] In one embodiment, the core 111 may have a diameter of 10 nm to 50 nm in at least one direction. By having the above structure, when the structure 10 is placed in the dispersion liquid 20 described below, an excellent Raman scattering effect can be provided.

[0063] In one embodiment, the second plasmonic metal shell layer 112 includes a second plasmonic metal, and the width of the plasmon resonance peak at the surface of the second plasmonic metal can be narrower than the width of the plasmon resonance peak at the surface of the first plasmonic metal. By narrowing the width of the plasmon resonance peak at the surface of the second plasmonic metal, as in the above structure, it is possible to provide better sensitivity when acquiring Raman scattering signals when the structures 10 are dispersed in a dispersion liquid 20, which will be described later.

[0064] In this case, as an optional embodiment, the width of the plasmon resonance peak at the surface of the first plasmonic metal and the width of the plasmon resonance peak at the surface of the second plasmonic metal can be measured in the same environment.

[0065] In one embodiment, the second plasmonic metal shell layer 112 comprises a second plasmonic metal, such as, but not limited to, Au, Ag, Cu, Al, W, Pt, Ni, and Pd.

[0066] In one embodiment, the core 111 can include gold (Au) and the second plasmonic metal shell layer 112 can include silver (Ag). Silver (Ag) has a light-harvesting effect that is more than five times stronger than gold (Au), and a structure 10 including nanoparticles 11 having such a structure can provide an excellent surface-enhanced Raman scattering spectroscopy signal.

[0067] In one embodiment, the second plasmonic metal shell layer 112 may have a thickness of 10 nm to 70 nm in at least one direction. As another example, the thickness of the second plasmonic metal shell layer 112 may be 30 to 70 nm, 40 to 70 nm, 50 to 70 nm, 60 to 70 nm, 30 to 60 nm, 40 to 60 nm, or 50 to 60 nm. If the thickness of the second plasmonic metal shell layer 112 exceeds 70 nm, the size of the nanoparticles 11 disposed inside the structure 10 may become too large, which may reduce the reproducibility of surface-enhanced Raman scattering. If the thickness is less than 30 nm, the distance between the shell layer and the core 111 may become too narrow, which may reduce the reproducibility of surface-enhanced Raman scattering.

[0068] 1B, in one embodiment, the nanoparticles 11 may include a polymer coating layer 113 formed on the outside of the second plasmonic metal shell layer 112 and surrounding the second plasmonic metal shell layer 112. The polymer coating layer 113 imparts a negative charge to the surface of the nanoparticles 11, which can prevent the nanoparticles 11 from agglomerating together.

[0069] By having this structure, the nanoparticles 11 can be prevented from agglomerating in the step prior to forming the silica shell layer 12 during the manufacturing process of the structure 10, and furthermore, the silica shell layer 12 can be formed more easily.

[0070] In one embodiment, the surface of the metallic nanoparticles 11 may be coated with cetyltrimethylammonium chloride (CTAC), a surfactant, and polyvinylpyrrolidone (PVP), a polymer. CTAC can immobilize charged molecules on the surface of the nanoparticles 11 through electrostatic attraction, and PVP can immobilize various biomolecules on the surface through van der Waals attraction and chelation. Thus, the CTAC and PVP coated on the surface of the metallic nanoparticles 11 immobilize biomolecules in the blood onto the surface of the nanoparticles during the formation of a silica shell layer, allowing the biomolecules in the blood to be easily accommodated in the space within the silica shell layer.

[0071] In one embodiment, the polymer coating layer 113 is not particularly limited, and any polymer coating layer 113 that can be easily selected by a person skilled in the art should be considered to fall within the scope of the present invention.

[0072] Meanwhile, the polymer coating layer 113 may contain a water-soluble polymer compound, such as, but not limited to, polyvinylpyrrolidone, polyvinyl alcohol, polyfluorosulfonate, hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose acetate, and polyamide.

[0073] 1C and 1D, in one embodiment, the structure 10 may further include a biomolecular substance B disposed in the receiving space H. By disposing the biomolecular substance B inside the silica shell layer 12 as in the above structure, the biomolecular substance B disposed inside the receiving space H can come into contact with the nanoparticles 11, and a surface-enhanced Raman scattering spectroscopy signal can be obtained on the surface of the nanoparticles 11, as will be described later.

[0074] As used herein, the term "biomolecular substance" refers to molecules and / or ions present in living organisms, and may refer to molecules and / or ions synthesized and / or produced in common biological processes such as cell division, morphogenesis, or development.

[0075] Biomolecular substance B may include not only proteins, carbohydrates, lipids, nucleic acids, and minerals, but also small molecules such as primary metabolites, secondary metabolites, and natural products, and may include both endogenous and exogenous substances. Examples of biomolecular substance B include, but are not limited to, plasma CA19-9, amyloid beta40, and amyloid beta42.

[0076] Meanwhile, as in the above structure, the structure 10 according to one embodiment may include nanoparticles 11 that form a peak by non-specifically causing plasmon resonance on the surface with a biomolecular substance B. In this case, as an alternative embodiment, referring to FIG. 1E, different biomolecular substances B may be provided inside the structure 10. With this configuration, multiple surface-enhanced Raman scattering spectroscopy signals can be obtained from a single structure 10.

[0077] Meanwhile, the multiple surface-enhanced Raman scattering spectroscopic signals obtained can be compiled into a database (DB) through multiple measurements, and disease-specific peaks can be measured based on the databased signals. Furthermore, when used in diagnostic kits, it can provide the effect of accurately diagnosing diseases in a short period of time.

[0078] In one embodiment, the structure 10 can contain two or more types of biomolecular substances B. By separating and extracting the upper or lower region of the biological solution treated with the pretreatment solution, the dimensions of the overall surface-enhanced Raman scattering spectroscopy signal obtained can be diversified, and a more detailed database can be created for multiple different biomolecular substances B. Ultimately, a structure 10 can be provided that can obtain surface-enhanced Raman scattering spectroscopy signals more accurately.

[0079] 1A to 1E, in one embodiment, the structure 10 can include a silica shell layer 12. The silica shell layer 12 has an internal storage space H, and the nanoparticles 11 and the biomolecular substance B can be disposed in one region within the internal storage space H of the silica shell layer 12.

[0080] When nanoscale particles are dispersed in a liquid or the like, they can aggregate due to interactions (e.g., attractive forces) between the particles in the dispersion liquid 20. However, when the silica shell layer 12 surrounding each nanoparticle 11 is provided as in the above structure, the silica shell layer 12 can prevent interactions between the nanoparticles 11, thereby preventing the aggregation of the particles, and can also provide the effects of increasing the surface-enhanced Raman scattering spectroscopy signal and improving the reproducibility of the surface-enhanced Raman scattering spectroscopy signal, thereby stabilizing the measurement results.

[0081] Furthermore, the structure 10 of one embodiment does not necessarily require a substrate, position, or probe that specifically binds to the biomolecular substance B, and therefore, when the biomolecular substance B is located on or in contact with the surface of the nanoparticle 11, a considerable number of surface-enhanced Raman scattering spectroscopic signals of the biomolecular substance B disposed inside the structure 10 can be measured.

[0082] As described above, the measured surface-enhanced Raman scattering spectroscopic signals can be compiled into a database, which can ultimately provide a diagnostic kit for diagnosing diseases even in the absence of biomarkers.

[0083] In one embodiment, the silica shell layer 12 may refer to a shell layer formed primarily from silicon (Si) and oxygen (O), and the material is not particularly limited. Any silica shell layer 12 that can be easily selected by a person skilled in the art is considered to fall within the scope of the present invention. For example, a silica shell layer 12 formed by a polymerization reaction of TEOS is included, but is not limited to this example.

[0084] In one embodiment, the silica shell layer 12 can have a thickness of 20 to 30 nm, and in another optional embodiment, the thickness can be 20 to 29, 20 to 28, 20 to 27, 20 to 26, 20 to 25, 20 to 24, 20.5 to 30, 20.5 to 29, 20.5 to 28, 20.5 to 27, 20.5 to 26, 20.5 to 25, 20.5 to 24, 21 to 30, 21 to 29, 21 to 28, 21 to 27, 21 to 26, 21 to 25, 21 to 24, 21.5 to 30, 21.5 to 29, 21.5 to 28, 21.5 to 27, 21.5 26, 21.5-25, 21.5-24, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22-24, 22.5-30, 22.5-29, 22.5-28, 22.5-27, 22.5-26, 22.5-25, 22.5-24, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 23.5-30, 23.5-29, 23.5-28, 23.5-27, 23.5-26, 23.5-25, or 23.5-24.

[0085] Also, in an alternative embodiment, the thickness of the silica shell layer 12 may be 23.28 nm or 21.85 nm, and such thickness may vary depending on whether or not ethanol pretreatment is performed.

[0086] The composition for surface-enhanced Raman scattering spectroscopy will be described below.

[0087] FIG. 2A is a diagram showing a diagnostic solution used in a diagnostic method provided by one embodiment, and FIG. 2B is an enlarged view of region A of FIG. 2A.

[0088] 2A, another embodiment of the present invention provides a composition for surface-enhanced Raman scattering spectroscopy (hereinafter referred to as a "diagnostic solution") including a dispersion liquid 20 and a structure for surface-enhanced Raman scattering spectroscopy 10 (hereinafter referred to as a "structure") dispersed in the dispersion liquid 20. The composition can be used as a diagnostic solution 1 for surface-enhanced Raman scattering spectroscopy.

[0089] In one embodiment, the structures 10 may be dispersed within the dispersion liquid 20 of the diagnostic solution 1, and a more specific and detailed description of the structures 10 is provided in the above-described embodiment.

[0090] In one embodiment, the dispersion liquid 20 may refer to a liquid substance in which nanoscale particles can be dispersed. The dispersion liquid 20 is not particularly limited, and any liquid substance in which nanoparticles 11 can be dispersed that can be easily selected by a person skilled in the art should be considered to fall within the scope of the present invention. The dispersion liquid 20 may be, for example, water (H2O) or ethanol (EtOH), but is not limited to these examples.

[0091] In one embodiment, the diagnostic solution 1 may further include an additive, such as a surfactant, which may help the nanoscale particles and / or the structures 10 described above to be more uniformly dispersed within the dispersion 20.

[0092] In one embodiment, the surfactant is not particularly limited, and cationic surfactants and / or anionic surfactants can be used, and any surfactant that can be easily selected by a person skilled in the art should be considered to fall within the scope of the present invention. Meanwhile, surfactants include, but are not limited to, CTAB, CTAC, etc.

[0093] A method for manufacturing the surface-enhanced Raman scattering spectroscopy structure 10 and the diagnostic solution for surface-enhanced Raman scattering spectroscopy 1 will be described below.

[0094] 3A and 3B are a flowchart illustrating a method for fabricating a surface-enhanced Raman scattering spectroscopy structure provided in accordance with one embodiment.

[0095] Referring to FIG. 3A, in order to solve the above technical problem, one embodiment of the present invention provides a method for manufacturing a structure for surface-enhanced Raman scattering spectroscopy (hereinafter referred to as the "structure manufacturing method"), which includes step S10 of forming a solution in which nanoparticles 11 are dispersed, and step S20 of forming a silica shell layer 12 surrounding the nanoparticles 11.

[0096] In addition, in one optional embodiment, the method for manufacturing the structure can include growing nanoparticles 11 on the solution and forming a silica shell layer 12 surrounding the nanoparticles 11, thereby providing a method for manufacturing a diagnostic solution 1 for surface-enhanced Raman scattering spectroscopy.

[0097] In one embodiment, step S10 of forming a solution having nanoparticles 11 dispersed therein can include a step of mixing a first solution containing a first precursor compound including a first plasmonic metal with a second solution containing a second precursor compound including a second plasmonic metal to form a mixed solution.

[0098] By mixing the first precursor compound and the second precursor compound, a first plasmonic metal of the first precursor compound can be grown on the core 111, and a second plasmonic metal of the second precursor compound can be grown on the outer surface of the core 111 to form a second plasmonic metal shell layer 112. This can form a core-shell nanoparticle 11.

[0099] For more specific and detailed descriptions of the first plasmonic metal and the second plasmonic metal, refer to the descriptions in the above-described embodiments.

[0100] On the other hand, the step of forming the core-shell nanoparticles 11 is not particularly limited, and any method that can be easily selected by a technician having ordinary knowledge in this technical field should be interpreted as falling within the scope of the present invention.

[0101] In one embodiment, the first precursor compound may refer to a compound that includes a first plasmonic metal and can form nanoscale nanoparticles containing the first plasmonic metal. This is not particularly limited, and any nanoparticle precursor compound that can be easily selected by a person skilled in the art should be considered within the scope of the present invention. Examples of the first precursor compound include, but are not limited to, HAuCl4·3H2O.

[0102] In one embodiment, the second precursor compound may refer to a compound that includes a second plasmonic metal and can form nanoscale nanoparticles or nanoparticle shells containing the second plasmonic metal. This is not particularly limited, and any nanoparticle precursor compound that can be easily selected by a person skilled in the art is considered to be within the scope of the present invention. Examples of the second precursor compound include, but are not limited to, AgNO3.

[0103] In one embodiment, when the first solution and the second solution are mixed, one or more of a reducing agent and a surfactant may be mixed in. When the mixed solution is formed, the first precursor compound forms the cores 111 of the nanoparticles 11 through nano-growth, and mixing one or more of a reducing agent and a surfactant in the first solution can further stimulate the growth of the nanoparticles 11.

[0104] The reducing agent and surfactant are not particularly limited, and any reducing agent and surfactant that can be easily selected by a person skilled in the art should be considered to fall within the scope of the present invention, such as NaBH4, CTAB, and CTAC, respectively.

[0105] In one embodiment, the method for fabricating a structure may further include mixing the mixed solution with a coating solution containing a water-soluble polymer compound. When the water-soluble polymer compound is mixed with the mixed solution containing the nanoparticles 11, the water-soluble polymer compound forms a polymer coating layer 113 on at least a portion of the surface of the nanoparticles 11, thereby preventing the nanoparticles 11 from agglomerating together.

[0106] In one embodiment, examples of the water-soluble polymer compound include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol, polyfluorosulfonate, hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose acetate, and polyamide.

[0107] The polymer coating layer 113 also allows biomolecular substances to be easily positioned on the metal surface, providing better sensitivity when acquiring Raman signals. For example, blood contains a variety of biomolecular substances, such as nucleic acids, proteins, organic substances, and inorganic substances, and the polymer coating layer 113 can be applied to the surface of the nanoparticles to act as an intermediate substance that can facilitate molecular interaction between the nanoparticles and biomolecules, allowing these biomolecular substances to be positioned between the metallic nanoparticles and the silica shell layer.

[0108] Biomolecular substances in the blood can be attached to the intermediate substance coated on the surface of the metallic nanoparticles through intermolecular interactions, and the process of forming a silica shell layer begins on the surface to which the biomolecules are not attached.In the process of enveloping the metallic nanoparticles, the biomolecules are fixed in a non-detached state, and as a result, various biomolecular substances in the blood can exist in the storage space between the metallic nanoparticles and the silica shell layer.

[0109] Meanwhile, in order to form the polymer coating layer 113 on the surface of the nanoparticles 11, as an alternative embodiment, the mixed solution may be formed and then mixed after a predetermined time.

[0110] In one embodiment, the method for manufacturing a structure may further include a step of mixing a coating solution containing a polymer compound having a unit represented by the following Chemical Formula 1 with the mixed solution, and as an optional embodiment, may further include a step of mixing a coating solution containing a water-soluble polymer compound having a unit represented by the following Chemical Formula 1:

[0111] [Chemical formula 1] JPEG2025537592000002.jpg4147

[0112] In one embodiment, the method for manufacturing a structure may include a step of mixing a solution or a mixed solution in which nanoparticles 11 are dispersed with a third solution containing a biomolecular substance B and a fourth solution containing a silica precursor compound. By mixing the solution containing nanoparticles 11 with the biomolecular substance B and the silica precursor compound and allowing them to react, the nanoparticles 11 and the biomolecular substance B can be arranged together inside the silica shell layer 12.

[0113] In one embodiment, the biomolecular substance B and the silica precursor compound can be mixed and reacted in a solution containing nanoparticles 11 using a stirrer, and as an alternative example, they can be mixed and reacted using an orbital shaker or a seesaw shaker.

[0114] For more specific and detailed explanations of the biomolecular substance B, refer to the explanations in the above-described embodiments.

[0115] In one embodiment, the silica precursor compound may refer to a compound capable of forming a silica shell layer 12 after reaction, and is not particularly limited thereto. Any silica precursor compound that can be easily selected by a person skilled in the art is considered to be within the scope of the present invention. Examples of such compounds include, but are not limited to, TEOS.

[0116] 3B, in one embodiment, the third solution containing the biomolecular substance B may be a solution treated with a pretreatment solution (S15). The pretreatment solution may contain a substance with low polarity, and as an optional example, may contain a substance with lower polarity than water.

[0117] The third solution can be produced by treating and / or processing a solution extracted directly from a living organism (hereinafter referred to as a "biological solution"), such as plasma, tissue fluid, or urine.

[0118] These biological solutions can use water (HO) as a solvent, and when a pretreatment solution containing a substance with low polarity is mixed with the biological solution, the biological molecule substances B with different molecular weights in the biological solution can be separated by molecular weight.

[0119] In one embodiment, the substance having a lower polarity than water may be, for example, an aprotic substance, methanol, ethanol, acetone, DMSO, etc., but is not limited to the above examples. Any substance having a lower polarity than water that can be easily selected by a person skilled in the art should be considered to fall within the scope of the present invention.

[0120] In one embodiment, the third solution may contain two or more types of biomolecular substances B.

[0121] By separating and extracting the upper or lower region of the biological solution treated with the pretreatment solution, the dimensions of the overall surface-enhanced Raman scattering spectroscopic signal obtained can be diversified, enabling a more detailed database to be created for the biomolecular substance B. Ultimately, a structure 10 can be provided that can more accurately diagnose diseases.

[0122] It goes without saying that the above-described embodiments of the present invention can be applied in combination with each other.

[0123] In yet another aspect, the present invention relates to a diagnostic method and a diagnostic system using surface-enhanced Raman scattering spectroscopy.

[0124] 4A and 4B are flowcharts of a diagnostic method using surface-enhanced Raman scattering spectroscopy provided by one embodiment.

[0125] Referring to FIG. 4A, in order to solve the above technical problem, one embodiment of the present invention can provide a diagnostic method using surface-enhanced Raman scattering spectroscopy (hereinafter referred to as "this diagnostic method"), which includes an irradiation step S100 of irradiating light onto a diagnostic solution 1 containing a biomolecular substance B to obtain a surface-enhanced Raman scattering spectroscopy signal, and a step S200 of analyzing the obtained surface-enhanced Raman scattering spectroscopy signal to diagnose a target disease.

[0126] In a living body with a specific disease, there may be biomolecular substances that appear specifically in response to the specific disease. A diagnostic method can be provided for diagnosing a target disease using specific surface-enhanced Raman scattering spectroscopic signals (hereinafter referred to as "spectroscopic signals") obtained from such biomolecular substances.

[0127] As will be described later, a diagnostic method according to one embodiment may include a step (not shown) of acquiring a first spectroscopic signal from a biological solution extracted from a patient suffering from a disease or a solution containing the biological solution. In addition, the first spectroscopic signals may be acquired from patients suffering from various diseases, and spectroscopic information relating to spectroscopic signals specific to the type of disease may be stored in a database in a data storage unit 140 (described later) or the like.

[0128] Target diseases include, but are not limited to, pancreatic cancer, Alzheimer's disease, rheumatism, coronavirus, influenza, and Alzheimer's disease.

[0129] In one embodiment, the biological solution refers to a fluid present in a human body, such as blood, plasma, tissue fluid, lymph, urine, etc. Furthermore, the biological solution is not limited to the above examples, and any bodily fluid that can be easily extracted by a layperson, a technician with ordinary skill in the art, a medical professional, or a medical assistant should be considered to fall within the scope of the present invention.

[0130] A diagnostic method according to one embodiment may include an irradiation step S100 of irradiating a diagnostic solution 1 containing a biomolecular substance B with light to obtain a spectroscopic signal. As described above, such a diagnostic solution may contain a surface-enhanced Raman scattering spectroscopy structure dispersed therein, and a surface-enhanced Raman scattering spectroscopy composition containing the surface-enhanced Raman scattering spectroscopy structure 10 (hereinafter referred to as "structure") dispersed therein may be used. Furthermore, such a diagnostic solution may be transported in a prepared state, or may be manufactured at the site where a disease is diagnosed. For a more specific and detailed description of the diagnostic solution, please refer to the description of the structure 10 and the composition containing the structure 10 dispersed in the above-described embodiment.

[0131] In one embodiment, a second spectroscopic signal can be obtained by irradiating light onto the diagnostic solution 1 containing the biomolecular substance B. At this time, as will be described later, the second spectroscopic signal can be compared and analyzed with spectroscopic information stored in the data storage unit 140 or the like, thereby determining which disease the diagnostic solution is for. In an optional embodiment, the above-described comparative analysis process can be used to identify the biomolecular substance B dissolved or dispersed in the diagnostic solution.

[0132] As described above, in one embodiment of the present invention, the diagnostic method directly irradiates light onto a liquid diagnostic solution to obtain a spectroscopic signal, and does not require a separate drying process, thereby significantly reducing the time required for diagnosis.

[0133] In addition, the diagnostic method provided in one embodiment diagnoses diseases by directly irradiating light L onto the liquid diagnostic solution 1, and therefore, compared to existing diagnostic methods, there is a possibility that contamination of the experimental environment will not occur as much. Furthermore, the structure 10, which is dispersed in a liquid state and will be described later, can maintain a similar environment even when repeated experiments are performed, thereby improving reproducibility.

[0134] Furthermore, the diagnostic solution 1 used in the diagnostic method according to one embodiment can be stored and transported in a liquid state, thereby ensuring convenient storage and transportation of the diagnostic solution 1. Furthermore, since the diagnostic solution 1 is manufactured in a liquid state, mass production of the diagnostic solution 1 is also possible.

[0135] In one embodiment, the light L irradiated onto the diagnostic solution 1 can be light in a wavelength band and intensity used for surface-enhanced Raman scattering or Raman scattering, such as, but not limited to, laser light.

[0136] 2A, in one embodiment, the diagnostic solution 1 can include a dispersion liquid 20 and structures 10 dispersed in the dispersion liquid 20. As in the above structure, in the present invention, the diagnostic solution 1 is not dried, and the structures 10 dispersed in a liquid state are irradiated with light L to acquire a spectroscopic signal, thereby improving the reproducibility and accuracy of the signal.

[0137] In addition, the diagnostic solution 1 can be produced by mixing it with a biological solution extracted from a patient suffering from a disease, thereby allowing the diagnostic solution 1 to contain the biomolecular substance B within the structure 10 contained therein.

[0138] 2B, the structure 10 can contain a biomolecular substance B in one region inside the structure 10, and when light is irradiated between the biomolecular substance B disposed inside the structure 10 and the one region of the structure 10, a surface plasmon phenomenon occurs, and a specific second spectroscopic signal S corresponding to the type of biomolecular substance B can be generated in the one region of the structure 10. These second spectroscopic signals S can be compared and analyzed with the above-mentioned spectroscopic information to diagnose target diseases.

[0139] 2B, one region inside the structure 10 can contain mutually different biomolecular substances B1 to B4. In this manner, the mutually different biomolecular substances B1 to B4 generate mutually different spectroscopic signals S1 to S4. Furthermore, the spectroscopic signals S1 to S4 generated at this time are spectroscopic signals generated specifically by the biomolecular substances B1 to B4.

[0140] The spectroscopic signals can be compared with the spectroscopic information described above to diagnose the target disease. Furthermore, as an optional embodiment, the spectroscopic signals S1 to S4 can be analyzed to identify the biomolecular substances B1 to B4.

[0141] 1A to 1E, by providing a silica shell layer 12, the structures 10 do not aggregate with each other and can be well dispersed in the dispersion liquid 20. Furthermore, by arranging the nanoparticles 11 including the plasmonic metal and the biomolecular substance B together inside the silica shell layer 12, a surface-enhanced Raman scattering spectroscopic signal can be generated more efficiently between the nanoparticles 11 and the biomolecular substance B.

[0142] Referring again to Figures 1E and 2B, in one embodiment, the biomolecular substance B may include two or more types of biomolecular substances B1 to B4. When different types of biomolecular substances B are included, specific surface-enhanced Raman scattering spectroscopic signals S1 to S4 corresponding to the biomolecular substances B may be generated.

[0143] In one embodiment, the second plasmonic metal shell layer 112 is shown in the form of a cube in the drawings, but the second plasmonic metal shell layer 112 may have a regular polyhedron structure other than a cube, and the regular polyhedron may include, for example, at least one of a regular octahedron, a regular dodecahedron, and a regular icosahedron.

[0144] In one embodiment, the second plasmonic metal shell layer 112 includes a second plasmonic metal, and the width of the plasmon resonance peak at the surface of the second plasmonic metal can be narrower than the width of the plasmon resonance peak at the surface of the first plasmonic metal.

[0145] As in the above structure, by narrowing the width of the plasmon resonance peak at the surface of the second plasmonic metal, when the structure 10 is dispersed in the dispersion liquid 20, it is possible to provide better sensitivity when acquiring a surface-enhanced Raman scattering spectroscopy signal.

[0146] In this case, as an optional embodiment, the width of the plasmon resonance peak at the surface of the first plasmonic metal and the width of the plasmon resonance peak at the surface of the second plasmonic metal can be measured in the same environment.

[0147] 1A to 1E, in one embodiment, nanoparticle 11 may include core 111, second plasmonic metal shell layer 112, and polymer coating layer 113 surrounding second plasmonic metal shell layer 112. Polymer coating layer 113 imparts a negative charge to the surface of nanoparticle 11, preventing nanoparticles 11 from agglomerating together.

[0148] By having this structure, the nanoparticles 11 can be prevented from agglomerating before the silica shell layer 12 is formed during the manufacturing process of the structure 10, and further, the silica shell layer 12 can be more easily formed. A more detailed description of the structure 10 is provided in the relevant embodiments described above.

[0149] In one embodiment, the structure 10 can be formed by mixing and reacting a solution in which the nanoparticles 11 are dispersed, a solution containing the biomolecular substance B, and a solution containing a silica precursor compound. A more detailed description of the method for producing the structure 10 is provided in the relevant embodiments described above.

[0150] In one embodiment, the solution containing biomolecular substance B may be, for example, a biological solution extracted from an organism or a solution in which biomolecular substance B is mixed with a solvent, but is not limited to such examples. On the other hand, the solution containing biomolecular substance B may include a pretreated solution, and the solution used in such a pretreatment process may be pretreated using a solution with a lower polarity than water.

[0151] By carrying out such a pretreatment process, the solution containing the biomolecular substance B can have various chemical or physical environments, and the dimensions of the acquired overall surface-enhanced Raman scattering spectroscopic signal can be diversified, thereby enabling the creation of a more detailed database for the biomolecular substance B. Ultimately, it is possible to provide a structure 10 that can acquire surface-enhanced Raman scattering spectroscopic signals more accurately.

[0152] In one embodiment, the substance having a lower polarity than water may be, for example, an aprotic substance, methanol, ethanol, acetone, DMSO, etc., but is not limited to the above examples. Any substance having a lower polarity than water that can be easily selected by a person skilled in the art should be considered to fall within the scope of the present invention.

[0153] In one embodiment, the method for preparing the structure 10 is not particularly limited, and any method for preparing the structure 10 that can be easily selected by a person skilled in the art is considered to be within the scope of the present invention. For example, the structure 10 can be prepared using the principle of nano-growth of metal particles in a solution, by mixing a solution containing core-shell nanoparticles 11 with a solution containing TEOS and a biomolecular material. Preferably, the structure 10 can be prepared according to the method for manufacturing the surface-enhanced Raman scattering spectroscopy structure and diagnostic method described above.

[0154] 4A again, the diagnostic method may include step S200 of diagnosing a target disease by analyzing the second spectral signal acquired through the diagnostic solution 1 in step S100. In this case, as an optional embodiment, the method may include step S220 of diagnosing a target disease by comparing and analyzing the second spectral signal acquired from the diagnostic solution with the spectral information in step S210 (see FIG. 4B).

[0155] As described above, biomolecular substances that appear specifically in response to a particular disease may be distributed within the body of a patient suffering from the particular disease. A spectroscopic signal specific to the biomolecular substance B within the structure 10 according to one embodiment can be acquired, and by analyzing this signal, the target disease can be diagnosed. In this case, as an optional embodiment, the biomolecular substance B can be identified, and the target disease can be diagnosed based on this.

[0156] A diagnostic method according to an embodiment may include a step (not shown) of acquiring a first spectroscopic signal from a biological solution extracted from a patient suffering from a specific disease or a solution containing the biological solution. As an alternative example, the first spectroscopic signal may be compiled into a database, and spectroscopic information may be stored in the data storage unit 140 or the like.

[0157] In this case, the method for acquiring the first spectroscopic signal is not particularly limited, and any surface-enhanced Raman scattering method in the form of nanoparticles, substrate, liquid, or solid can be used. Any other surface-enhanced Raman scattering spectroscopic signal acquisition method that can be easily selected by a technician having ordinary knowledge in this technical field should be construed as falling within the scope of the present invention.

[0158] Furthermore, as an optional embodiment, the method may include a step of acquiring a spectroscopic signal for biomolecular substance B, and storing the spectroscopic information by creating a database of the spectroscopic signal for biomolecular substance B. In this case, the databased spectroscopic information can be stored in the data storage unit 140 in an embodiment described below.

[0159] In another alternative embodiment, the step of creating a database of biomolecular substances B may include creating a database of biomolecular substances B that cause any disease by acquiring spectroscopic signals using target bacteria and / or viruses that cause any disease.

[0160] Depending on the type of disease, specific biomolecular substances B may exist in the body, and the target disease can be diagnosed by multifaceted analysis of the type of biomolecular substance B. As mentioned above, such biomolecular substances B could be not only proteins and sugars, but also bacteria and viruses.

[0161] Meanwhile, in one embodiment, referring again to Figure 2B, the biomolecular substance B may include two or more different types of biomolecular substances B. Depending on the type of disease, biomolecules that are specifically generated in vivo may also include two or more types of biomolecular substances B. By identifying the biomolecular substance B in this way, the accuracy and reproducibility of the diagnosis of the target disease can be further improved.

[0162] In one embodiment, the first and second spectroscopic signals may be compared and analyzed by comparing and checking peak intensity, degree of agreement, specific wave numbers, and the like.

[0163] For example, when comparing the first and second spectroscopic signals, in the case of a pancreatic cancer patient, the surface-enhanced Raman scattering signal is obtained at 1453 cm -1 , 878cm -1 , 1517cm -1 , 1385cm -1 , 1303cm -1 , 1153cm -1 , 1184cm -1 , 1043cm -1 , 669cm -1 , 435cm -1 The diagnostic solution may have a spectroscopic signal appearing at a peak at 1453 cm -1 , 878cm -1 , 1517cm -1 , 1385cm -1 , 1303cm -1 , 1153cm -1 , 1184cm -1 , 1043cm -1 , 669cm -1 , 435cm -1 If a spectroscopic signal appears, the biomolecular material contained in the diagnostic solution can be diagnosed as belonging to a patient with pancreatic cancer.

[0164] In one embodiment, the diagnostic method may further include a step of comparing with a control group, which may consist of the same solvent as the diagnostic solution 1, to determine whether the spectroscopic signals obtained using the diagnostic solution 1 were obtained during normal operation of the diagnostic system 100.

[0165] On the other hand, the step of comparing with the comparative experimental group is not particularly limited, and any method that can be selected by a technician having ordinary knowledge in this technical field should be interpreted as falling within the scope of the present invention.

[0166] 5A-5C are block diagrams illustrating a diagnostic system 100 provided according to one embodiment.

[0167] In order to solve the above technical problem, another embodiment of the present invention provides a disease diagnostic system 100 using surface-enhanced Raman scattering spectroscopy (hereinafter referred to as "this diagnostic system").

[0168] Referring to FIG. 5A, the diagnostic system 100 provided in one embodiment may include a container portion 110 in which a diagnostic solution 1 is placed, an irradiation portion 120 that irradiates light onto the diagnostic solution 1 placed in the container portion 110 to acquire a spectroscopic signal in a region of the structure 10, and a diagnostic portion 130 that analyzes the acquired spectroscopic signal.

[0169] In one embodiment, the diagnostic system 100 may further include a manufacturing unit that manufactures the structure 10. In the manufacturing unit, the structure 10 having the biomolecular substance B contained in one region inside can be manufactured.

[0170] In this case, in an optional embodiment, the manufacturing unit can manufacture the diagnostic solution 1 having the structures 10 dispersed therein. The manufactured diagnostic solution 1 can be used in the container unit 110, the irradiation unit 120, etc., which will be described later.

[0171] On the other hand, the method for manufacturing the structure 10 in the manufacturing department is not particularly limited, and a more specific and detailed description of the method for manufacturing the structure 10 is substituted for the description in the above-described embodiment.

[0172] In one embodiment, the diagnostic solution 1 includes a structure 10. The diagnostic system 100 can directly irradiate the diagnostic solution 1 with light via an irradiation unit 120 to obtain a spectroscopic signal in a region of the structure 10 disposed in the diagnostic solution 1, and can analyze the spectroscopic signal in a diagnostic unit 130 to diagnose a target disease.

[0173] Meanwhile, the structure 10 may contain a biomolecular substance B as described above, and a more specific and detailed description thereof is provided in the above-described embodiment.

[0174] In one embodiment, the container 110 may be configured to receive the diagnostic solution 1, and the diagnostic solution 1 received in the container 110 may be irradiated with light to generate a spectroscopic signal in a region of the structure 10. It is preferable to receive a sufficient amount of the diagnostic solution 1, and as an optional example, the container 110 receiving the diagnostic solution 1 may be at least 200 μL, although it is of course not limited to this size.

[0175] On the other hand, the container portion 110 is not particularly limited and can be easily selected by a technician having ordinary knowledge in the art, and any container that can contain a liquid and generate a spectroscopic signal should be interpreted as falling within the scope of the present invention.

[0176] In one embodiment, the irradiation unit 120 is configured to irradiate light onto the diagnostic solution 1. When the diagnostic solution 1 is irradiated with light, a spectroscopic signal is generated in one region within the structure 10 disposed within the diagnostic solution 1.

[0177] In this case, as an optional embodiment, the structure 10 can include nanoparticles 11, a biomolecular substance B, and a silica shell surrounding them. Also, the spectroscopic signal can be generated near the surface where the biomolecular substance B and the nanoparticles 11 come into contact. Meanwhile, a more specific and detailed description of the structure 10 is provided in place of the description in the above-described embodiment.

[0178] 5A again, in one embodiment, the irradiating unit 120 may include an irradiating unit that emits light. The irradiating unit is not particularly limited, and in one optional embodiment, may include a laser irradiating unit.

[0179] 5B, in one embodiment, the diagnostic unit 130 can diagnose a target disease by comparing and analyzing the spectroscopic information in the above embodiment with the second spectroscopic signal. In an optional embodiment, the biomolecular substance B contained in the diagnostic solution 1 can be identified during this process.

[0180] On the other hand, when the diagnostic unit 130 uses information on the spectroscopic signal, the spectroscopic information of the first spectroscopic signal stored in the data storage unit 140 (described later) can be used.

[0181] In one embodiment, the diagnosis unit 130 may use an algorithm for comparing and / or analyzing the degree of coincidence of peak wavenumbers, peak intensity, degree of coincidence, etc. between the spectroscopic information and the second spectroscopic signal, and may search for the first spectroscopic signal through the above process, and may diagnose a target disease that specifically corresponds to the searched first spectroscopic signal.

[0182] Referring to FIG. 3C, in one embodiment, the diagnosis unit 130 may include a first diagnosis unit 130a that searches for a first spectroscopic signal corresponding to the second spectroscopic signal among the spectroscopic information, and a second diagnosis unit 130b that diagnoses a disease using the searched first spectroscopic signal.

[0183] Referring again to FIG. 5B, in one embodiment, the diagnostic system 100 can include a data store 140 for acquiring spectroscopic signals and storing spectroscopic information.

[0184] In one embodiment, the data storage unit 140 can store the spectroscopic information of the first spectroscopic signal. The diagnosis unit 130 can search for the first spectroscopic signal corresponding to the second spectroscopic signal in the spectroscopic information by comparing the spectroscopic information stored in the data storage unit 140 with the second spectroscopic signal. Furthermore, a specific disease can be searched for through the first spectroscopic signal, thereby enabling the diagnosis unit 130 to diagnose the target disease.

[0185] 5B and 5C again, in one embodiment, the data storage unit 140 may include a first data storage unit 140a that stores spectroscopic information of the first spectroscopic signal. The spectroscopic information may be, for example, a spectral chart of the surface-enhanced Raman scattering spectroscopic signal for a specific disease, spectral intensity, setting values ​​of the irradiator, etc., and is not limited to the above examples.

[0186] In one embodiment, the data storage unit 140 may include a second data storage unit 140b that stores information about the disease and the first spectroscopic signal. The diagnosis unit 130 can diagnose the target disease using the information stored in the second data storage unit 140b.

[0187] As an optional embodiment, the data storage unit 140 can store information about the biomolecular substance B in a database. Such information about the spectroscopic signal of the biomolecular substance B may be, for example, a specific Raman scattering spectroscopic signal generated by a type of protein, bacterium, virus, inorganic substance, etc. The description of the method for acquiring such information is substituted for the description of the above-mentioned embodiment.

[0188] Meanwhile, in one embodiment, the data storage unit 140 and the diagnosis unit 130 may communicate with each other using a wired / wireless communication method, and a diagnosis system 100 that diagnoses diseases by a short-distance / long-distance method through such a method can be provided. Meanwhile, such a wired / wireless communication method is not particularly limited, and any communication method that can be easily selected by a person skilled in the art should be considered to fall within the scope of the present invention.

[0189] It goes without saying that the above-described embodiments of the present invention can be applied in combination with each other.

[0190] Hereinafter, manufacturing examples, embodiments, and experimental examples of the present invention will be described. However, it is clearly understood that these manufacturing examples, embodiments, and experimental examples are intended to more specifically explain the configurations and effects of the present invention, and that the scope of the present invention is not limited thereto. Embodiment Embodiment 1 - Structures containing nanoparticles with core-shell structure

[0191] In this embodiment 1, a surface-enhanced Raman scattering spectroscopy structure and a composition for surface-enhanced Raman scattering spectroscopy in which the structure is dispersed were produced. The specific production process is as follows:

[0192] To produce a surface-enhanced Raman scattering spectroscopy structure and a surface-enhanced Raman scattering spectroscopy composition in which the structure is dispersed, nanoparticles are formed, and then a biomolecular substance located near the formed nanoparticles and a silica shell layer surrounding them are formed together. (1) Core-shell nanoparticle formation

[0193] To form 2-3 nm gold nanoparticles capped with CTAB, 9.75 ml of 100 mM CTAB solution was prepared, to which 250 μl of 10 mM HAuCl4·3H2O solution and 600 μl of 10 mM NaBH4 solution were added. The mixture was stirred for 2 minutes and then allowed to react for 3 hours.

[0194] Next, to grow the 2-3 nm-sized gold nanoparticles capped with CTAB into 30 nm gold nanoparticles, 16 mL of 200 mM CTAC solution was prepared, and then 16 mL of 0.5 mM HAuCl4·3H2O solution and 16 mL of 0.8 mM ascorbic acid solution were added to 40 μL of the prepared CTAB-capped AuNP seeds and allowed to react for 7 days.

[0195] Next, to form core-shell nanoparticles by forming a silver second plasmonic metal shell layer on the surface of the prepared 30 nm gold nanoparticles, 10 mL of 1.0 mM AgNO3 solution and 10 mL of 25 mM ascorbic acid solution were added to 10 mL of the formed 30 nm AuNP solution and reacted for 40 minutes. After centrifugation, the solution was redispersed in triple distilled water to form gold-silver core-shell nanoparticles. (2) PVP coating on the surface of core-shell structured nanoparticles

[0196] After preparing 10 mL of the Au-Ag core-shell nanoparticle solution formed as described above, 0.5 mL of 1 v / v% SDS solution and 5 mL of 2.5% (w / v) PVP solution were added and reacted for 10 minutes. After centrifugation, the nanoparticles were redispersed in distilled water, thereby forming core-shell nanoparticles with a PVP coating layer on the surface. (3) Formation of biomolecular material and silica shell layer

[0197] To form the core-shell nanoparticles with the PVP coating layer formed as described above, the biomolecular substances located near the nanoparticles, and the silica shell layer surrounding them, the following steps were performed: In Example 1.1, plasma was pretreated with ethanol before the surface-enhanced Raman scattering spectroscopy structure was manufactured, and in the following Example 1.2, plasma that had not undergone the pretreatment step was used to manufacture the surface-enhanced Raman scattering spectroscopy structure. Embodiment 1.1 - Pretreatment

[0198] After preparing 10 μL of plasma, 20 μL of deionized water and 70 μL of ethanol (EtOH) were added and reacted for 10 minutes, thereby carrying out a plasma pretreatment step.

[0199] 17.5 μL of core-shell nanoparticles with a PVP coating layer formed thereon were added to 20 μL of ethanol-pretreated plasma supernatant, 44.5 μL of deionized water, and 20 μL of 0.05 v / v% TEOS solution, and the mixture was reacted for 30 minutes. Then, 20 μL of 10 v / v% DMA solution was added to prepare a composition for surface-enhanced Raman scattering spectroscopy in which the structures for surface-enhanced Raman scattering spectroscopy were dispersed. Embodiment 1.2 - No pretreatment

[0200] 17.5 μL of core-shell nanoparticles with a PVP coating layer formed thereon were added to 2 μL of plasma not pretreated with ethanol, 60.5 μL of deionized water, and 20 μL of 0.05 v / v% TEOS solution, and the mixture was reacted for 30 minutes. Then, 20 μL of 10 v / v% DMA solution was added to prepare a composition for surface-enhanced Raman scattering spectroscopy in which structures for surface-enhanced Raman scattering spectroscopy were dispersed. Experimental example 1 - Confirmation of structure

[0201] In this Experimental Example 1, an experiment was carried out to confirm the state of the surface-enhanced Raman scattering spectroscopy structure manufactured through the above-described Embodiments 1.1 and 1.2. Experimental Example 1.1 - Check the size of nanoparticles

[0202] In Experimental Example 1.1, an experiment was conducted to confirm the size of nanoparticles. The specific experimental method was to measure the size of nanoparticles using dynamic light scattering and to take TEM images.

[0203] Dynamic light scattering measurements of the nanoparticles revealed that the spherical gold nanocores had a diameter of 31 nm and a PI of 0.16, while the cubic gold-silver core-shell nanoparticles had a diameter of 47.5 nm and a PI of 0.25.

[0204] Referring to the TEM image in FIG. 6A, the width of the gold-silver core-shell nanoparticles was measured to be about 30 nm, confirming the presence of a spherical gold core inside a cubic silver metal shell layer. Experimental Example 1.2 - Confirmation of the silica shell layer

[0205] In Experimental Example 1.2, an experiment was conducted to confirm whether a silica shell layer was formed on the surface of the structure. The specific experimental method was to measure the size of the nanoparticles using dynamic light scattering and take TEM images.

[0206] The diameter of the nanoparticles with a silica shell layer, as determined by dynamic light scattering, was 90.25 nm with a PI of 0.35 when pretreated with ethanol, and 87.4 nm with a PI of 0.31 when not pretreated with ethanol. The thickness of the silica shell was 23.28 nm with ethanol pretreatment and 21.85 nm without pretreatment.

[0207] The TEM image in Figure 6B confirms that a silica shell layer was formed on the outside of the gold-silver core-shell structure, which consists of a gold core located in the center and a cubic silver metal shell layer surrounding the gold core. Experimental Example 1.3 - Identification of Biomolecular Substances

[0208] In Experimental Example 1.3, the Raman scattering spectra were compared between when a biological material was present inside the structure and when it was not.

[0209] The specific experimental method involved observing the difference in Raman spectra between PVP-coated silver (Ag) nanocube particles in which a plasma sample was added to form a silica shell (red) and those in which a silica shell was formed without adding a plasma sample (blue).

[0210] FIG. 7 is a diagram showing the experimental results of Experimental Example 1.3.

[0211] Referring to Figure 7, when examining the difference in Raman spectra between when a plasma sample, i.e., a biological material, is present in the nanostructure and when it is not, it can be seen that many peaks are newly generated or disappear in the spectrum. For example, at 1170 cm -1 , 1520cm -1 The peak at 930 cm is newly generated due to the presence of plasma. -1 , 1130cm -1 The peak disappears. Experimental Example 2: Experiment to confirm Raman spectrum with and without pretreatment

[0212] In Experimental Example 2, an experiment was carried out to confirm what difference occurs in the Raman spectrum depending on whether or not the pretreatment with ethanol is performed, through the above-mentioned Embodiments 1.1 and 1.2.

[0213] As a specific experimental method, a process of laminating a silica shell onto plasma and nanoparticles was carried out, and 70% ethanol and plasma were mixed in a ratio of 9:1 (v / v) and left for 10 minutes, after which a process of laminating a silica shell onto nanoparticles was carried out, and the Raman spectra of each were obtained and compared.

[0214] FIG. 8 shows Raman spectra showing the experimental results of Experimental Example 2.

[0215] Referring to Figure 8, comparing the case without pretreatment (blue) and the case with ethanol pretreatment (orange), the pretreatment case showed a 650cm -1 , 880cm -1There is a peak at 1280 cm without pretreatment. -1 , 1390cm -1 It can be seen that a peak exists at Experimental Example 3 - Confirmation of surface-enhanced Raman scattering spectroscopic signals for diagnosing target diseases

[0216] In Experimental Example 3, the diagnostic solution prepared in accordance with the first embodiment was used to obtain a surface-enhanced Raman scattering spectroscopic signal.

[0217] The diagnostic solution was placed in a 96-well plate, irradiated with a 532 nm laser, and the scattered light was captured using a Raman spectrometer. The results were the same as those shown in Figure 9. Experimental Example 4 - Confirmation of diagnostic error rate of target disease

[0218] In Experimental Example 4, the target disease was diagnosed using the spectroscopic signal obtained through Experimental Example 3. -1 , 878cm -1 , 1517cm -1 , 1385cm -1 , 1303cm -1 , 1153cm -1 , 1184cm -1 , 1043cm -1 , 669cm -1 , 435cm -1 After confirming the peaks shown in Fig. 1, it was possible to classify healthy individuals and cancer patients with an accuracy of 0.931, a sensitivity of 0.800, and a specificity of 0.800.

[0219] The above description of the present invention is for illustrative purposes only, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. Therefore, the above-described embodiments should be understood to be illustrative in all respects and not limiting. For example, each component described as a single component may be implemented in a distributed form, and similarly, components described as distributed may be implemented in a combined form. The scope of the present invention is defined by the claims that follow, and all modifications and variations derived from the meaning and scope of the claims and their equivalents should be construed as being within the scope of the present invention. [Explanation of symbols]

[0220] 1: Diagnostic solution 10: Structure 11: Nanoparticles 12: Silica shell layer 20:Dispersion liquid 100: Diagnostic System 110: Container part 111: Core 112: Second plasmonic metal shell layer 113: Polymer coating layer 120: Irradiation unit 130: Diagnostic Department 140: Data storage unit

Claims

1. a silica shell layer having an internal storage space; and nanoparticles comprising a plasmonic metal; The nanoparticles are disposed in a region of the accommodation space inside the silica shell layer.

2. the nanoparticles include a core comprising a first plasmonic metal and a second plasmonic metal shell layer surrounding the core, the second plasmonic metal shell layer comprising a second plasmonic metal; The surface-enhanced Raman scattering spectroscopy structure of claim 1 , wherein the second plasmonic metal shell layer has a symmetrical structure with respect to a center of the second plasmonic metal shell layer.

3. The structure for surface-enhanced Raman scattering spectroscopy according to claim 1 , wherein the structure includes a biomolecular substance disposed in the accommodation space.

4. 3. The surface-enhanced Raman scattering spectroscopy structure of claim 2, wherein the first plasmonic metal and the second plasmonic metal each independently comprise one or more selected from the group consisting of Au, Ag, Cu, Al, W, Pt, Ni, and Pd.

5. 3. The structure for surface-enhanced Raman scattering spectroscopy of claim 2, wherein a width of a plasmon resonance peak at a surface of the second plasmonic metal is narrower than a width of a plasmon resonance peak at a surface of the first plasmonic metal.

6. The surface-enhanced Raman scattering spectroscopy structure of claim 2 , wherein the second plasmonic metal shell layer has a regular polyhedron structure.

7. providing a solution in which nanoparticles are dispersed; forming a silica shell layer surrounding the nanoparticles dispersed in the solution; A method for manufacturing a structure for surface-enhanced Raman scattering spectroscopy, comprising:

8. preparing the solution in which the nanoparticles are dispersed includes mixing a first solution containing a first precursor compound including a first plasmonic metal with a second solution containing a second precursor compound including a second plasmonic metal to form a mixed solution; the nanoparticles include a core comprising a first plasmonic metal and a second plasmonic metal shell layer surrounding the core, the second plasmonic metal shell layer comprising a second plasmonic metal; The method for manufacturing a surface-enhanced Raman scattering spectroscopy structure according to claim 7 , wherein the second plasmonic metal shell layer has a symmetric structure with respect to a center of the second plasmonic metal shell layer.

9. The method for manufacturing a surface-enhanced Raman scattering spectroscopy structure according to claim 8 , further comprising the step of mixing a coating solution containing a water-soluble polymer compound with the mixed solution.

10. the step of forming the silica shell layer includes a step of mixing the mixed solution with a third solution containing a biomolecular substance and a fourth solution containing a silica precursor compound; 9. The method for manufacturing a surface-enhanced Raman scattering spectroscopy structure according to claim 8, wherein the silica shell layer is formed so that the nanoparticles and at least a part of the biomolecular substance are disposed inside the silica shell layer.

11. obtaining a first surface-enhanced Raman scattering spectroscopic signal from a biological solution extracted from a patient; A step of irradiating a diagnostic solution in which the surface-enhanced Raman scattering spectroscopy structure according to any one of claims 1 to 6 is dispersed with light, and acquiring a second surface-enhanced Raman scattering spectroscopy signal in one region of the surface-enhanced Raman scattering spectroscopy structure; comparing the first surface-enhanced Raman scattering signal with the second surface-enhanced Raman scattering signal to identify a disease in the patient; A method for diagnosing a disease using surface-enhanced Raman scattering spectroscopy, comprising:

12. The method for diagnosing diseases using surface-enhanced Raman scattering spectroscopy according to claim 11 , wherein the structure for surface-enhanced Raman scattering spectroscopy contains two or more types of biomolecular substances.

13. The diagnostic method includes a step of creating a database of first surface-enhanced Raman scattering spectroscopic signals obtained from the biological solution extracted from the patient. The method for diagnosing a disease using surface-enhanced Raman scattering spectroscopy according to claim 11, further comprising:

14. The diagnostic method includes the steps of acquiring a surface-enhanced Raman scattering spectroscopic signal for a biomolecular substance inside the surface-enhanced Raman scattering spectroscopic structure, and creating a database of information on the surface-enhanced Raman scattering spectroscopic signals for the biomolecular substance. The method for diagnosing a disease using surface-enhanced Raman scattering spectroscopy according to claim 11, further comprising:

15. a container portion in which a diagnostic solution is placed; an irradiation unit that irradiates the diagnostic solution placed in the container with light and generates a surface-enhanced Raman scattering spectroscopic signal in a region of the surface-enhanced Raman scattering spectroscopy structure according to any one of claims 1 to 6 contained in the diagnostic solution; a diagnostic unit for analyzing the generated surface-enhanced Raman scattering spectroscopic signal; A disease diagnostic system using surface-enhanced Raman scattering spectroscopy, comprising:

16. The disease diagnosis system using surface-enhanced Raman scattering spectroscopy according to claim 15 , wherein the surface-enhanced Raman scattering spectroscopy structure includes two or more types of biomolecular substances.

17. the diagnostic system includes a data storage unit that acquires the surface-enhanced Raman scattering spectroscopy signal and stores spectroscopic information for the surface-enhanced Raman scattering spectroscopy signal; 16. The disease diagnosis system using surface-enhanced Raman scattering spectroscopy according to claim 15, further comprising:

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