JP2016212117A - Apparatus having surface-enhanced spectroscopy element on exterior surface - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a system for performing surface-enhanced spectroscopy (SES), and a method for manufacturing an apparatus for performing the SES.SOLUTION: An apparatus for performing surface-enhanced spectroscopy (SES) includes an elongated substrate 102 having a shape and size to be inserted into a specimen, where the elongated substrate has a first end part 104 and a second end part 106. The apparatus also includes a plurality of surface-enhanced spectroscopy (SES) elements 110 positioned on an exterior surface of the elongated substrate at a location between the first end part 104 and the second end part 106 of the elongated substrate 102.SELECTED DRAWING: Figure 1A

Description

Background In surface-enhanced spectroscopy (SES), such as surface-enhanced Raman spectroscopy (SERS), the vibrational excitation level of an analyte is investigated. The energy of the photon can be shifted (shifted) by an amount equal to the amount of vibration level excited by the photon (Raman scattering). An analyte can be identified by detecting a Raman spectrum consisting of a wavelength distribution in a band corresponding to molecular vibrations specific to the analyte being investigated. In SERS, analyte molecules are in contact or proximity (eg, tens of nanometers) to metal nanoparticles that may or may not be coated with a dielectric (eg, silicon dioxide, silicon nitride, and polymers). And the metal nanoparticles support a plasmon mode (collective oscillation of free electron density) that, once excited by light, creates a strong near field around the metal nanoparticles. These fields can bind to analyte molecules in the near-field region and enhance the emission of scattered signals from the analyte molecules.

  The features of the present disclosure are shown by way of example and are not limited to the following drawings. In the drawings, like reference numerals indicate like elements.

FIG. 3 is a simplified side view of an apparatus for performing spectroscopy according to an example of the present disclosure. 1B is an enlarged cross-sectional view of the apparatus shown in FIG. 1A along line AA according to an example of the present disclosure. FIG. FIG. 1B is a simplified cross-sectional view of the apparatus shown in FIG. 1A according to another example of the present disclosure. FIG. 4 is a diagram of an apparatus for performing spectroscopy according to another example of the present disclosure. FIG. 4 is a diagram of an apparatus for performing spectroscopy according to another example of the present disclosure. FIG. 4 is a diagram of an apparatus for performing spectroscopy according to another example of the present disclosure. 1 is a diagram of a SES system that can include a SES apparatus and an apparatus for performing spectroscopy, according to an example of the present disclosure. FIG. FIG. 4 is an isometric view of an array of SES elements (in this case, nanofingers) that may be implemented in the apparatus shown in FIGS. 1A-3 according to an example of the present disclosure. FIG. 4B is a cross-sectional view taken along line CC shown in FIG. FIG. 4B is a cross-sectional view taken along line CC shown in FIG. 4A after the nanofinger has collapsed, according to an example of the present disclosure. 4 is a flow diagram of a method for fabricating an apparatus for performing spectroscopy according to an example of the present disclosure. 2 is a flow diagram of a method for using an apparatus for performing spectroscopy, according to an example of the present disclosure.

DETAILED DESCRIPTION For purposes of brevity and illustration, the present disclosure will be described primarily with reference to examples thereof. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. However, it will be readily apparent that the present disclosure may be practiced without being limited to these specific details. In addition, some methods and structures are not described in detail so as not to unnecessarily obscure the present disclosure.

  Throughout this disclosure, the terms “a (a) and (an)” are intended to indicate at least one particular element. As used herein, the term “comprising” means including, but not limited to. The term “based on” means based at least in part. Furthermore, the term “light” means electromagnetic radiation having wavelengths in the visible and invisible portions of the electromagnetic spectrum, including the infrared, near infrared, and ultraviolet portions of the electromagnetic spectrum.

  This specification includes an apparatus for performing spectroscopy (spectroscopy, spectroscopic inspection), a system for performing surface-sensitized spectroscopy (SES), a method for manufacturing the apparatus, and the apparatus. A method for performing spectroscopy is disclosed. The apparatus disclosed herein can include an elongated substrate having a shape and size that can be inserted into a specimen, wherein the elongated substrate includes a first end and a second end. Have. The apparatus can also include a plurality of SES elements disposed on the outer surface of the elongated substrate at a location between the first end and the second end of the elongated substrate. According to one example, the device can also include a cover layer to protect the SES element during insertion and / or infusion of the device into the specimen. The cover layer can include a porous membrane that is selectively removable and / or substantially prevents certain particles from contacting the plurality of SES elements.

  According to one example, the elongated substrate on which the SES element can be provided can be an acupuncture needle, in which case the SES element is provided near the insertion tip of the acupuncture needle. In one respect, the SES element can be placed at a desired location on the specimen in a relatively simple manner. That is, conventional techniques associated with inserting acupuncture needles may be utilized to insert the devices disclosed herein to place the SES element at the desired fluid location of the analyte.

  Further, SES elements can be provided around the outer periphery of the elongated substrate. As such, at least some of the SES elements can receive the illumination beam (excitation light) regardless of the rotational orientation in which the elongated substrate is inserted into the specimen. For one point, for example, even if the device is rotated about its central longitudinal axis, the device can still be used to perform spectroscopy.

  As an example, the devices disclosed herein can be implemented in medical management of health and illness. For example, the devices disclosed herein perform relatively rapid and accurate profiling (analyses) and discover biomarkers (biological indicators) from physiological analytes, as well as early diagnosis, disease Can be used to detect physiological conditions that are important for the prevention, screening, monitoring, diagnosis, treatment, and health improvement, particularly in the assessment and assessment of medical and drug treatments. As described herein, the device can identify single or multiple conditions and metrics, the distribution of specific biomarkers and naturally or artificially introduced reporter molecules, and potential biomarkers. It can be used to perform spectroscopy in real time (online) and / or offline to teach and collect the discovery of new or collective profiles.

  Referring initially to FIG. 1A, a simplified side view of an apparatus 100 for performing spectroscopy is shown, according to an example. It should be understood that the apparatus 100 shown in FIG. 1A can include additional components, and some of the components described herein can be removed without departing from the scope of the apparatus 100. And / or can be modified. It should also be understood that the components shown in FIG. 1A are not drawn to scale, and that the components are different from those shown herein, respectively. May have different relative sizes.

  Generally speaking, apparatus 100 includes surface-enhanced Raman spectroscopy (SERS), surface-sensitized luminescence detection, surface-sensitized fluorescence detection, or other types of surface-sensitized optically enhanced detection. Can be implemented to perform spectroscopy (spectroscopy). In this case, the apparatus 100 can include an elongated substrate 102 and a plurality of surface-sensitized spectroscopy (SES) elements 110. The SES element 110 is shown to extend slightly above the surface of the elongated substrate 102. However, as will be described in more detail below, the SES element 110 can be a relatively small element, for example, can have nanoscale dimensions, and therefore should be understood in some examples. , SES element 110 may not look the same as that shown in FIG. 1A. As such, it should be clearly understood that the depiction of SES element 110 in FIG. 1A and other drawings is for simplified illustration and description.

  The elongate substrate 102 can extend along the horizontal axis and can have a first end 104 and a second end 106. Each of the SES elements 110 may be provided in individual groups at a plurality of locations along the elongated substrate 102 between the first end 104 and the second end 106. Accordingly, the SES elements 110 shown in FIG. 1A can represent individual groups of SES elements 110, as described in more detail below.

  The device 100 can have a certain size, a certain configuration, and can be manufactured from a material that makes the device 100 suitable for insertion and / or injection into a specimen (specimen, specimen). The first end 104 can also have a pointed tip that generally allows the device 100 to be inserted through the skin layer of the specimen. However, the pointed tip may be omitted and the device 100 may be inserted by a conventional acupuncture cylindrical insertion tool. As a specific example, the elongate substrate 102 of the device 100 can be an acupuncture needle and thus can be inserted into a specimen in a manner similar to that utilized to insert an acupuncture needle into a human. The second end 106 of the elongated substrate 102 can include a handle (not shown) for facilitating insertion of the device 100 or at least a portion of the device 100 into the specimen.

  According to one example, the device 100 is implemented to perform spectroscopy in vivo, ie after inserting and / or injecting the device 100 into a specimen such as a human, animal, insect, plant, abiotic element, etc. obtain. Accordingly, the device 100 can be implemented to analyze particles (eg, molecules) of a liquid specimen such as blood, lymph, saliva, interstitial fluid, and the like. Alternatively, the device 100 can be implemented in a spectroscopic application that does not require injection of the device 100.

  Thus, the elongated substrate 102 can comprise any material suitable for insertion and / or injection into a specimen, such as silicon, polymer, plastic, silver, titanium, and the like. In other examples where the device 100 is to be implemented without being inserted and / or injected into the specimen, the elongated substrate 102 may also include other materials, such as materials that may be toxic to the specimen. it can. According to one example, the elongate substrate 102 can have a diameter (or width) that ranges from about 0.1 mm to about 10 mm and a length that ranges from about 1 mm to about 100 mm. Further, the SES elements 110 can be configured in groups that span a relatively small section of the elongated substrate 102. As an example, each group of SES elements 110 may have a width that ranges from about 5 μm (micron) to about 500 μm (micron).

  The SES element 110 can be provided on any surface of the elongated substrate 102. In particular, the SES elements 110 can be disposed on the elongated substrate 102 in different groupings. That is, one group of SES elements 110 can be placed at one location on the elongated substrate 102 and another group of SES elements 110 can be placed at a second location on the elongated substrate 102. However, it should be understood that the depiction of the device 100 is for illustration purposes, and that various changes to the components of the device 100 can be made without departing from the scope of the device 100. For example, the plurality of SES elements 110 may be arranged to include a staggered (alternate) configuration. As an example, a single group of SES elements 110 may be disposed along the surface of the elongated substrate 102. As another example, additional groups of SES elements 110 can be disposed along substantially the entire length of the elongated substrate 102.

  Generally speaking, the SES element 110 can be an element that enhances any emission of light, fluorescence, luminescence, etc. by particles in contact with and / or in close proximity to the SES element 110; Therefore, the detection operation is enhanced on the particles, such as surface enhanced Raman spectroscopy (SERS), enhanced photoluminescence, enhanced fluorescence emission, and the like. The SES element 110 includes plasmonic nanoparticles or nanostructures that can include, but are not limited to, materials that support plasmons such as gold (Au), silver (Ag), and copper (Cu). be able to. The SES element 110 can also include structures disposed on the substrate in a variety of ordered or random configurations.

  The SES element 110 can have a nanoscale surface roughness, which is generally characterized by nanoscale surface features on the surface of the layer (s), and a material layer that supports plasmons It can be created naturally during the deposition (s). As defined herein, a plasmon-supporting material can be a material that facilitates the generation or emission of signals from an analyte on or near the material during signal scattering and spectroscopy. .

  In some examples, the SES element 110 can be functionalized to facilitate the adsorption of analyte molecules. For example, the surface of the SES element 110 can be functionalized such that a particular class of analyte can be attracted and bound or selectively adsorbed onto the SES element 110. Various ways in which the SES element 110 can enhance scattered light emission from the analyte molecules are described in more detail below.

  The apparatus 100 can include a relatively large number of SES elements 110 to significantly enhance the enhancement of signal emission from the analyte (eg, Raman scattered light, luminescence, fluorescence, etc.). Further, the plurality of SES elements 110 may include any suitable dimensions sufficient for the SES element 110 to significantly enhance signal emission and sufficient for a detector to detect the emitted signal. .

  Referring now to FIG. 1B, a simplified vertical cross-sectional view of the device 100 along line AA of FIG. 1A is shown, according to an example. The elongate substrate 102 has a circular cross section, and the SES element 110 can extend around the circumference of the elongate substrate 102. Furthermore, this configuration of SES elements 110 around the circumference of the elongated structure 102 allows light to be directed onto the group of SES elements 110 regardless of the rotational orientation of the elongated substrate 102 along the longitudinal axis of the elongated substrate 102. The possibilities can be greatly increased.

  It should be understood that the device 100 shown in FIG. 1B can be modified in various ways without departing from the scope of the device 100. For example, instead of extending over the entire circumference of the elongated substrate 102, the SES element 110 may be provided on a portion of the circumference of the elongated substrate 102. As an example, the SES element 110 may be provided on half the circumference of the elongated substrate 102. As another example, the SES elements 110 may be arranged in multiple groups around the circumference of the elongate substrate 102. In this example, gaps may be provided between individual groups of SES elements 110 along the circumference of the elongated substrate 102.

  Referring now to FIG. 1C, a simplified vertical cross-sectional view of the apparatus 100 according to another example is shown. In the example shown in FIG. 1C, the elongated substrate 102 is shown as having a rectangular cross-section, and the SES element 110 is shown as being disposed on one side of the elongated substrate. It should be understood that the elongate substrate 102 can have other cross-sectional shapes without departing from the scope of the device 100. For example, the elongated substrate 102 can have other polygonal shapes, oval shapes, and the like. Further, although the elongate substrate 102 is shown as having a solid structure, the elongate substrate 102 can alternatively have a fully or partially hollow structure. Additionally or alternatively, the SES element 110 may be provided along multiple surfaces of the elongated substrate 102.

  Referring now to FIG. 2A, a simplified side view of the apparatus 100 for performing the spectroscopy shown in FIG. 1A according to another example is shown. The device 100 shown in FIG. 2A can include all of the same components that are included in the device 100 shown in FIG. 1A, and therefore, these components are included in the device 100 shown in FIG. 2A. Will not be described in more detail.

  As shown in FIG. 2A, the device 100 can include a cover layer 200 extending over the SES element 110. The cover layer 200 can also extend around the circumference of the elongated substrate 102, as shown in FIG. 2B, which is a vertical cross-sectional view of the device 100 along line BB of FIG. 2A. The device 100 of FIG. 2B is also shown to include optional pores 210, described in more detail below. According to one example, the cover layer 200 can be a protective layer that can protect the SES element 110 during insertion of the device 100 into a specimen. Additionally or alternatively, the cover layer 200 can protect the SES element 110 after injection into the specimen of the device 100. In any case, the cover layer 200 may be formed from any suitable material for protecting the SES element 110. For example, the cover layer 200 can be formed from biodegradable materials that are harmless to humans, combinations of biocompatible materials including artificial and biopolymer materials, metals, lipids, carbohydrates, and the like.

  According to certain examples, the cover layer 200 can be formed from a material that can dissolve after being inserted into the specimen. In this example, the cover layer 200 may be formed of a material and a specific size that allows the cover layer 200 to dissolve after exposure to the analyte fluid after a predetermined length of time. According to another example, the cover layer 200 can be formed of a material that can be removed when an external stimulus is applied on the cover layer 200. In this example, external stimuli can include, for example, light, heat, chemicals, biological agents, and the like. Thus, for example, external stimuli can be applied on the cover layer 200 after insertion and / or injection of the device 100 into the specimen. Thus, in one respect, the cover layer 200 can protect the SES element 110 during insertion and / or injection into the specimen and can be removed to expose the SES element 110 after insertion and / or injection.

  According to another example, the cover layer 200 can include a drug that can be delivered to the analyte. In this example, the cover layer 200 may additionally or alternatively be provided over an area of the substrate 102 where the SES element 110 is not provided. As a further example, the cover layer 200 can cover the drug material so that the drug can be delivered to the specimen when the cover layer 200 is removed. Thus, for example, the cover layer 200 of these examples can be removed subsequent to performing a spectroscopic operation indicating that the drug will be delivered to the analyte.

  According to a further example, the cover layer 200 can include a porous membrane having a plurality of pores 210 (FIG. 2B). The cover layer 200 in this example can substantially prevent various materials from contacting the SES element 110 under the cover layer 200. Therefore, only particles having a size small enough to manage to pass through the pores 210 of the cover layer 200 can contact the SES element 110. In one respect, the cover layer 200 can substantially prevent larger unwanted particles from blocking or damaging the SES element 110. The pores 210 can also have a specific shape to allow selective passage of molecules having a specific shape. Additionally or alternatively, the cover layer 200 can be functionalized with a receptor for molecules that are not expected to pass through the pores 210. In this example, the cover layer 200 can be functionalized with receptors of various types of molecules so that multiple species of fluids can be selectively and efficiently blocked.

  Also, the cover layer 200 can be formed to allow light, including excitation light and scattered signals, to pass substantially through. In this example, the cover layer 200 may be formed and / or formed of an optically transparent material so as to have a sufficiently thin size to allow light and signals to pass through. As a specific example, the cover layer 200 can have a thickness between about 2 nm and about 500 nm. Further, although the cover layer 200 is shown as having a relatively thin configuration, the cover layer 200 may alternatively have a thicker sponge-like or skeleton-like matrix configuration.

  The cover layer 200 in this example may be composed of any suitable material that allows the cover layer 200 to perform the functions of the device 100 described herein. Examples of suitable materials for the cover layer 200 include cellulose acetate, urethane-based polymers (eg, polyurethane, polyether urethane, or polycarbonate urethane), ethylene glycol-based polymers, heparin functionalized polymers, combinations of these materials, and the like. obtain.

  As an example, the pores 210 may be fabricated into the cover layer 200 through an implementation of molecular imprinting technology. For example, in this technique, molecules that are to be allowed to pass through the cover layer 200 are mixed with a polymeric material, and the mixture is formed into a relatively thin sheet and resist cured (eg, UV cured). Also good. The molecules are then dissolved from a relatively thin sheet of mixed material, thereby leaving the pores 210 shaped specifically to fit the molecules that will be allowed to pass through the cover layer 200. It is. A thin sheet of material can then be placed on a supporting porous sublayer (not shown) and the combined layers can be placed on top of the SES element 110.

  According to another example, the cover layer 200 includes a lipid bilayer that can be a thin polar membrane made from two layers of lipid or phospholipid molecules. A lipid bilayer can include a relatively flat sheet of lipid molecules that forms a continuous barrier around cells. The lipid bilayer can include proteins or channels that serve as transport excipients through the lipid bilayer membrane. In this regard, proteins can selectively transport molecules, for example, molecules have a small enough size to pass through the lipid bilayer membrane through the lipid bilayer membrane, and thus lipids. It can allow the bilayer membrane to act as a filter. Lipid bilayers can be harvested from naturally occurring cells and / or can be made synthetically from lipid molecules. In any case, the lipid bilayer can be disposed, for example, by coating the lipid bilayer on a supported porous sublayer (not shown), and the combined layers can be disposed on the SES element 110. .

  According to a further example, the cover layer 200 can be functionalized to include host molecules such as crown ethers, cyclodextrins, etc. that will be bound to the corresponding guest molecules. Since the molecule corresponding to the host molecule can bind to the host molecule, the corresponding guest molecule can be substantially prevented from passing through the cover layer 200 and contacting the SES element 110.

  Referring now to FIG. 2C, a simplified side view of the apparatus 100 for performing the spectroscopy shown in FIG. 2A is shown, according to another example. The device 100 shown in FIG. 2C may differ from the device 100 shown in FIG. 2A in that the device 100 can include multiple cover layers 210a and 210b. In particular, each of the cover layers 210a and 210b can cover an area on an individual set of SES elements 110.

  According to one example, each of the cover layers 210a and 210b is formed of a material that can dissolve at different rates or be photodegraded by light after the cover layers 210a and 210b are exposed to the analyte fluid. And / or have a different configuration (eg, thickness). In this example, different sets of SES elements 110 may be exposed to the analyte fluid at different times or to light for photolysis.

  In another example, the cover layers 210a and 210b may be formed from the same material and have the same configuration. In this example, external stimuli can be applied to the cover layers 210a and 210b at different times to expose different sets of SES elements 110 contained under the cover layers 210a and 210b. By selectively exposing different groups of SES elements 110 at different times, the device 100 can be used to detect changes in the state of the analyte over time.

  As shown in FIGS. 2A-2C, the cover layers 200, 210 a, 210 b can extend a distance over the surface of the elongated substrate 102. However, the cover layers 200, 210a, 210b can include relatively thin layers and thus the device 100 can be inserted into the specimen without substantial interference from the cover layers 200, 210a, 210b. It becomes possible. It should be understood that in some examples, the cover layers 200, 210a, 210b may not look the same as shown in FIGS. 2A-2C. As such, it should be clearly understood that the depiction of the cover layers 200, 210a, 210b of FIGS. 2A-2C is for simplified illustration and description.

  Referring now to FIG. 3, a diagram of a SES system 300 including a SES device 302 and device 100 for performing SES is shown, according to an example. It should be understood that the SES system 300 shown in FIG. 3 can include additional components, and some of the components described herein do not depart from the scope of the SES system 300. Can be removed and / or modified. It should also be understood that the components shown in FIG. 3 are drawn not to scale, and that the components are different from those shown in this specification, respectively. May have different relative sizes.

  The SES device 302 can include an illumination light source 304, a dichroic beam splitter 308, a reflector 310, and a spectrometer 314. The illumination source 304 can emit an illumination beam 306 (eg, a laser beam, an LED beam, or other type of light beam) through a dichroic beam splitter 308. The illumination beam 306 can also be reflected onto the device 100 by the reflector 310. The illumination beam 306 can illuminate the analyte layer 320 to illuminate the SES element 110 and target particles that are relatively close to and / or in contact with the SES element 110.

  In FIG. 3, target particles 340 are shown contained within a fluid flow 330 that may include, for example, blood, lymph, saliva, interstitial fluid, and the like. The target particles 340 can include, for example, natural and / or artificially introduced reporter molecules, biomarkers (biomarkers), and the like. Generally speaking, biomarkers and reporter molecules can be derived from molecular indicators of blood and other body fluids, as well as conformation and chemical parameters of medical parameters related to health and disease. The fluid flow 330 can include target particles 340 and other bodily fluids. When the fluid 330 flows near the device 100, some of the target particles 340 may contact some of the SES elements 110 and possibly couple with some of the SES elements 110.

  Generally speaking, the illumination beam 306 can act as excitation light for the SES element 110, thereby creating a near field around the SES element 110. A near field around the SES element 110 can couple to a target particle 340 in the vicinity of the SES element 110. Also, the metal nanoparticles (or other plasmonic structures) of the SES element 110 can act to enhance the single release process of the target particles 340. As a result, a scattered signal 312 (eg, Raman scattered light, luminescence, fluorescence emission, etc.) can be emitted from the target particle 340, and the emission of the scattered signal 312 can be enhanced by the SES element 110. A portion of the scattered signal 312 that may be emitted in all directions from the target particle 340 near the SES element 110 may be emitted toward the reflector 310.

  Device 100 may be inserted and / or injected under a layer of specimen 320 (eg, skin layer, body tissue, vein wall, blood vessel, lymphatic trunk, lid, etc.) into which device 100 may be inserted and / or injected. Shown to be. In another example, the illumination beam 306 can pass through a gaseous or liquid environment in which the apparatus 100 can be placed. In any case, the scattered signal 312 can also pass through the surface layer and / or the gaseous or liquid environment.

  Scattered signal 312 can be directed back from reflector 310 and back to dichroic beam splitter 308. The dichroic beam splitter 308 can also reflect the scattered signal 312 toward the spectrometer 314. The spectrometer 314 can include optical elements such as slits, diffraction gratings, lenses, etc. that allow the separation and measurement of light of different wavelengths. Further, the spectrometer 314 is a detector (for example, a photomultiplier tube (PMT), a charge coupled device (CCD), a complementary metal oxide semiconductor (CMOS), etc.) for measuring the intensity of the separated wavelength region. Detector). The measured intensity of the separated wavelength band can be used to identify the analyte.

  Various changes can be made to the SES device 302 shown in FIG. 3 without departing from the scope of the SES system 300. For example, the reflector 310 can have a parabolic shape that can focus the illumination beam 306 onto the SES element 110 and / or focus the scattered signal 312 onto the dichroic beam splitter 308. As a further example, various additional optical components (e.g., mirrors, prisms, optical fibers, etc.) may be placed to direct the illumination beam 306 onto the SES element 110 and / or the scattered signal. 312 can be directed to the spectrometer 314.

  4A-4C, an isometric view and a side view, respectively, of an array 400 of SES elements 110 are shown, according to an example. It should be understood that the array 400 shown in FIGS. 4A-4C can include additional components, some of which are described herein are disclosed herein. It can be removed and / or modified without departing from the scope of the apparatus 100. It should also be understood that the components shown in FIGS. 4A-4C are drawn to scale and are not the same as those shown herein. Each may have a different relative size.

Generally speaking, the array 400 of SES elements 110 shown in FIGS. 4A-4C is an example of the plurality of SES elements 110 shown in FIGS. 1A-3. In particular, in the array 400, the SES element 110 can be placed on top of individual nanofingers 404 that extend above the surface of the substrate 402. Substrate 402 can be silicon, silicon nitride, glass, plastic, _{polymer, SiO 2, Al 2 O 3} , such as a combination of aluminum or the like, or these materials may be formed from any suitable material. The substrate 402 can be the elongate substrate 102 shown in FIG. 1A or the substrate 402 can be a separate substrate that can be placed on top of the elongate substrate 102.

  According to one example, the nanofinger 404 can have a dimension that is in the nanometer range, for example, a dimension that can be less than about 500 nm, as described in more detail below, where the nanofinger 404 is bent laterally. It can be formed of a relatively flexible material that allows it to be collapsed or collapsed, for example allowing the tips of the nanofinger 404 to move towards each other. Examples of suitable materials for nanofinger 404 include UV curable or thermosetting imprinting resists, polyalkyl acrylates, polysiloxanes, polydimethylsiloxane (PDMS) elastomers, polyimides, polyethylenes, polypropylenes, polyurethanes, fluoropolymers, etc. Alternatively, polymeric materials such as or any combination thereof, metallic materials such as gold, silver, aluminum and the like, semiconductor materials, and the like, and combinations thereof may be included.

  Nanofinger 404 can be attached to the surface of substrate 402 through any suitable attachment mechanism. For example, nanofinger 404 can be grown directly on the surface of substrate 402 through the use of various suitable nanostructure growth techniques. As another example, the nanofinger 404 can be integrally formed with the substrate 402. In this example, for example, a portion of the material from which the substrate 402 can be manufactured can be etched or otherwise processed to form the nanofinger 404. In a further example, a separate layer of material can be deposited on the surface of the substrate 402 and the separate layer of material can be etched or otherwise processed to form the nanofinger 404. In various examples, the nanofinger 404 can be manufactured through a nanoimprinting or embossing process, in which case a relatively rigid column in a multi-stage imprinting process on a polymer matrix to form the nanofinger 404. The template can be used. In these examples, the template can be formed through photolithography or other advanced lithography with the desired patterning to align the nano fingers 404 in a predetermined configuration. More specifically, for example, a desired pattern can be designed into a mold by any of electron beam lithography, photolithography, laser interference lithography, focused ion beam (FIB), spherical self-assembly, and the like. Furthermore, the pattern can be transferred onto another substrate, such as silicon, glass, or a polymer substrate (PDMS, polyimide, polycarbonate, etc.). Various other processes, such as etching, and various techniques used in the manufacture of microelectromechanical systems (MEMS) and nano-electromechanical systems (NEMS) are also used to fabricate nanofinger 404. be able to.

  Nanofinger 404 is shown having a substantially cylindrical cross-section. However, it should be understood that the nanofinger 404 can have other shaped cross-sections, such as, for example, rectangular, square, triangular, and the like. Additionally or alternatively, the nanofinger 404 can be formed with features such as notches, bulges, etc., such that the nanofinger 404 is tilted so that it substantially falls in a particular direction. Thus, for example, two or more adjacent nanofingers 404 can include features to increase the likelihood that the nanofingers 404 will fall toward each other. Various ways in which the nanofinger 404 can collapse are described in more detail below.

  The array 400 can include a substantially random distribution of nano fingers 404 or a predetermined configuration of nano fingers 404. In any case, according to one example, the nanofinger 404 can be brought into a state where the tips of at least two adjacent nanofinger 404 are close to each other when the nanofinger 404 is in a partially collapsed state. As such, they can be disposed relative to each other. As a specific example, adjacent nanofingers 404 can be positioned less than about 100 nm from each other. According to certain examples, nanofinger 404 may be patterned on substrate 402 such that adjacent ones of nanofinger 404 are preferentially collapsed into a predetermined geometric shape (eg, triangle, square, pentagon, etc.). .

  Referring now to FIG. 4B, a cross-sectional view of the array 400 along line CC shown in FIG. 4A is shown, according to an example. As shown in that figure, each of the tips 408 of the nanofinger 404 can include an individual SES element 110 disposed thereon. The SES element 110, which can include metal nanoparticles, is one of, for example, physical vapor deposition (PVD), chemical vapor deposition (CVD), sputtering, etc. of metal materials, or pre-synthesized nano Through the self-assembly of particles (self-assembly), it can be deposited on the tip 408 of the nanofinger 404.

  Although nano-finger 404 is shown in FIGS. 4A-4B as each extending perpendicular to and at the same height relative to each other, some of nano-finger 404 extends at various angles and heights relative to each other. It should be understood that this is acceptable. Differences in the angle and / or height of the nanofinger 404 may occur due to differences arising from manufacturing or growth variations that exist, for example, in the fabrication of the nanofinger 404 and the deposition of the SES element 110 on the nanofinger 404. .

  As shown in FIG. 4B, the nano fingers 404 can be in a first position where the tips 408 can be in a substantially constant array with respect to each other. The gap 410 between the tips 408 can be of a size large enough to allow liquid to be placed in the gap 410. In addition, the gap 410 may be configured such that at least some of the tips 408 of the nanofinger 404 are in contact with each other as the liquid provided to the gap 410 evaporates, for example through capillary forces applied to the tips 408 as the liquid evaporates. It can be of a size that is small enough to allow it to be pulled towards.

  Referring now to FIG. 4C, a cross-sectional view along line CC shown in FIG. 4A of the array 400 is shown after evaporation of the liquid, according to an example. The view shown in FIG. 4C is the same as the view shown in FIG. 4B, except that several tips 408 of nanofinger 404 can be in a second position drawn toward each other. It may be. According to one example, the tips 408 of some nanofinger 404 are due to capillary forces applied to each of the adjacent nanofinger 404 during and after evaporation of a liquid (not shown) in the gap 410 between the tips 408. Thus, they can be in relatively close proximity to each other over a period of time and remain in that state. Further, the SES elements 110 on adjacent tips 408 can be bonded to each other through, for example, gold-gold bonds (bonding), bonding molecules (not shown), and the like.

  In one respect, the tips 408 of the nanofinger 404 can be pulled toward each other as shown in FIG. 4C to enhance signal emission by the target particle 340 in the near field of the SES element 110. . The reason is that a relatively small gap (or no gap) between SES elements 110 on adjacent tips 408 forms a “hot spot” having a relatively large electric field strength. According to one example, nanofinger 404 can be placed in the partially collapsed state shown in FIG. 4C prior to introduction of fluid flow 330 (FIG. 3) containing target particles 340. According to another example, the nanofinger 404 collapsed partially as shown in FIG. 4C before forming the cover layers 200, 210a, 210b on the SES element 110 shown in FIGS. 2A-2C. Can be placed into a state.

  According to a further example, the SES element 110 can be deposited and / or formed directly on the substrate 402. Additionally or alternatively, the SES elements 110 are such that the SES elements 110 are in contact with each other or relatively close to each other and the SES elements 110 can be transferred to another substrate, such as the elongated substrate 102. Can be initially formed and placed, for example, as shown in FIG. 4C.

  Referring now to FIG. 5, a flowchart of a method 500 for manufacturing an apparatus 100 for performing spectroscopy is shown, according to an example. It should be understood that the method 500 shown in FIG. 5 can include additional processes without departing from the scope of the method 500, and some of the processes described herein are eliminated. And / or may be modified. Further, although specific reference is made herein to apparatus 100 as manufactured through an implementation of method 500, method 500 was configured differently without departing from the scope of method 500. It should be understood that the device can be implemented to manufacture.

  At block 502, a plurality of SES elements 110 can be provided on the surface of the elongate substrate 102 having a shape and size that can be inserted into the specimen, where the elongate substrate 102 comprises the first end 104 and It has a second end 106. The first end 104 can have a pointed tip. As described above, the SES element 110 may be provided on the surface of the elongated substrate 102 in any of a variety of ways.

  In block 504, cover layers 200, 210 a, 210 b may be provided on the elongated substrate 102. According to one example, cover layers 200, 210a, 210b may be provided on the SES element 110 to protect the SES element 110 during insertion and / or after injection of the device 100 into the specimen. Additionally or alternatively, the cover layers 200, 210a, 210b can include a drug to be delivered to the specimen.

  Referring now to FIG. 6, a flowchart of a method 600 for using the apparatus 100 for performing spectroscopy is shown, according to an example. It should be understood that the method 600 shown in FIG. 6 can include additional processes without departing from the scope of the method 600, and some of the processes described herein are eliminated. And / or may be modified. Further, although specific reference is made herein to apparatus 100 as used in method 600, method 600 uses apparatus configured differently without departing from the scope of method 600. It should be understood that it can be done.

  At block 602, at least a portion of the device 100 can be inserted into an analyte, the analyte containing a target particle 340 such that at least some of the target particles contact the plurality of SES elements 110. 330 is included. According to the example where the elongate substrate 102 of the device 100 is an acupuncture needle, the device 100 can be inserted into the specimen in a manner similar to that utilized to insert the acupuncture needle into the specimen. For example, the device 100 can be inserted directly through the outer layer (eg, skin) of the specimen without requiring the use of a separate delivery mechanism.

  In block 604, stimuli may optionally be applied on the cover layers 200, 210a, 210b to at least partially remove the cover layers 200, 210a, 210b. As described above, the stimulus can include any of heat, light, chemicals, biological agents, and the like. Further, applying a stimulus in block 604 may include, for example, a cover layer 200 from a material and / or configuration that dissolves or is photodegraded by light after the cover layers 200, 210a, 210b are exposed to the analyte fluid. , 210a, 210b can be optional. In other examples where the cover layers 200, 210 a, 210 b are formed from a porous membrane, the cover layers 200, 210 a, 210 b can be maintained on the SES element 110.

  At block 606, the illumination beam can be directed (sent) onto the plurality of SES elements 110 and the target particle 340, thereby causing the target particle 340 to emit a scattered signal 312. As described above, the SES element 110 can generally enhance the emission of the scattered signal 312 from the target particles 340 that are in contact with or relatively close to the SES element 110. In addition, the scattered signal 312 can be sent to a spectrometer 314.

  At block 608, the scattered signal 312 emitted by the target particle 340 may be measured. Scattered signal 312 can be measured by spectrometer 314 as described above in connection with FIG.

  Although specifically described throughout this disclosure, representative examples of this disclosure are useful across a wide range of applications, and the above description is not intended to be limiting and should not be construed as such, It is provided as an illustrative description of aspects of the present disclosure.

What has been described and illustrated herein are examples along with some of its variations. The terms, descriptions and figures used herein are set forth by way of illustration only and are not meant as limitations. Many variations are possible within the spirit and scope of the present contents (and their equivalents), which are intended to be defined by the following claims, in which all terms are Their broadest reasonable meaning is intended unless otherwise indicated.

Claims (15)

An apparatus for performing spectroscopy,
An elongate substrate having a shape and size that can be inserted into a specimen, the elongate substrate having a first end and a second end;
A plurality of surface enhanced spectroscopy (SES) elements disposed on an outer surface of the elongated substrate at a location between the first end and the second end of the elongated substrate;
A cover layer covering the plurality of SES elements to protect the plurality of SES elements during insertion of the elongated substrate into the specimen.   The apparatus of claim 1, wherein the elongated substrate comprises an acupuncture needle.   The elongate substrate has a circular cross section, and the plurality of SES elements are inserted into the specimen at a location between the first end and the second end of the elongate substrate. The apparatus according to claim 1, wherein the apparatus is disposed around an outer periphery of the elongated substrate to receive an irradiation beam regardless of rotational orientation.   The apparatus according to claim 1, further comprising a plurality of nanofingers extending from an outer surface of the elongated substrate, wherein the plurality of SES elements are disposed at tips of the plurality of nanofingers.   The plurality of nanofingers includes the plurality of nanofingers such that tips of adjacent nanofingers are in close proximity to each other and the plurality of SES elements at at least some of the tips of the adjacent nanofingers contact each other. The apparatus of claim 4, wherein the apparatus collapses partially over adjacent nanofingers.   The apparatus of any of claims 1-5, wherein the cover layer can be removed to expose the plurality of SES elements after insertion of the elongated substrate into the specimen.   The device according to any one of claims 1 to 6, wherein the cover layer is at least one soluble in the analyte fluid, photodegradable, and removable by receiving an external stimulus.   The device according to claim 1, wherein the cover layer is made of a porous membrane that can substantially prevent specific particles from coming into contact with the plurality of SES elements.   The plurality of groups of the plurality of SES elements are disposed on the surface of the elongated substrate at a plurality of different locations between the first end and the second end of the elongated substrate. The apparatus in any one of 1-7. The cover layer is
A first cover layer covering a first group of the plurality of SES elements;
A second cover layer covering a second group of the plurality of SES elements;
The apparatus of claim 9, wherein the first cover layer and the second cover layer are removable separately relative to each other.   The apparatus of claim 10, wherein the first cover layer and the second cover layer are adapted to be removed at different rates or at different times.   The method further comprising: a medicinal material provided on the elongate substrate, wherein the medicinal material can be introduced into the specimen after a predetermined amount of time and at least one when subjected to an external stimulus. The apparatus according to any one of 11. A system for performing spectroscopy using the apparatus according to claim 1,
An illumination light source for illuminating the plurality of SES elements;
And a spectrometer for detecting light emitted from an analyte disposed proximate to the plurality of SES elements. A method for performing spectroscopy using the apparatus according to claim 1,
Contacting at least some of the target particles with the plurality of SES elements in a fluid of the analyte containing the target particles;
Directing an irradiation beam to the plurality of SES elements and the target particle, causing the target particle to emit a scattering signal;
Measuring the scattering signal emitted by the target particle. A method for manufacturing the device according to claim 1,
Providing the plurality of SES elements on the outer surface of the elongated substrate;
Providing the cover layer on the elongated substrate.

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