WO2019148759A1 - Sers单元及其制备方法与应用 - Google Patents

Sers单元及其制备方法与应用 Download PDF

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WO2019148759A1
WO2019148759A1 PCT/CN2018/093164 CN2018093164W WO2019148759A1 WO 2019148759 A1 WO2019148759 A1 WO 2019148759A1 CN 2018093164 W CN2018093164 W CN 2018093164W WO 2019148759 A1 WO2019148759 A1 WO 2019148759A1
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sers
nano
nanoparticles
sers unit
unit according
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PCT/CN2018/093164
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English (en)
French (fr)
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郭清华
孙海龙
卢荻
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苏州天际创新纳米技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
    • C25D11/02—Anodisation
    • C25D11/04—Anodisation of aluminium or alloys based thereon
    • C25D11/18—After-treatment, e.g. pore-sealing
    • C25D11/24—Chemical after-treatment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
    • C25D11/02—Anodisation
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
    • C25D11/02—Anodisation
    • C25D11/04—Anodisation of aluminium or alloys based thereon
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
    • C25D11/02—Anodisation
    • C25D11/04—Anodisation of aluminium or alloys based thereon
    • C25D11/045—Anodisation of aluminium or alloys based thereon for forming AAO templates
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
    • C25D11/02—Anodisation
    • C25D11/26—Anodisation of refractory metals or alloys based thereon
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G01N21/658—Raman scattering enhancement Raman, e.g. surface plasmons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites

Definitions

  • the invention relates to a Surface-Enhanced Raman Scattering (SERS) technology, in particular to a chip for surface enhanced Raman detection and a preparation method and application thereof.
  • SERS Surface-Enhanced Raman Scattering
  • SERS Surface-Enhanced Raman Scattering
  • SPR surface plasmon resonance
  • the level of SERS activity is closely related to the structure of the SERS chip (also known as the SERS substrate), especially the nanostructures thereon.
  • SERS chips such as electrochemical rough metal electrodes or nanoparticle agglomerates formed by dripping of noble metal nanosols, due to the randomness of their nanostructures, resulting in non-uniform SERS signals, poor signal repeatability of target molecules, seriously affecting SERS The development and application of technology.
  • a series of SERS substrates with regular nanostructures were prepared.
  • CN103590037A discloses a single-layer film structure SERS substrate having a highly regular nanostructure with excellent uniformity and high reproducibility and reliability.
  • the enhancement factor (EF) only 106, which limits its application in trace analysis.
  • Some researchers have prepared nanoparticle aggregates by atomic evaporation, magnetron sputtering, pulse deposition or electrochemical deposition, and obtained higher enhancement factors, but the preparation process is complicated, the controllability is poor, and the cost is high, which makes it difficult to achieve. Scale and promote the application.
  • a first aspect of the present invention provides a SERS unit, comprising: a substrate having a plurality of nano-recesses distributed on a surface thereof; a plurality of nanoparticle aggregates, each of the nanoparticle aggregates being composed of a plurality of The nanoparticles are aggregated and each nanoparticle aggregate is respectively limited by a corresponding nano-recess.
  • the nano-depressions include, but are not limited to, nanopits, nanopores, and the like.
  • the distance between two adjacent said nano-recessed portions is not more than 100 nm, preferably not more than 50 nm, more preferably 10 nm to 30 nm.
  • the nanoparticle aggregates are formed by self-assembly of the nanoparticles in the liquid phase.
  • the driving forces for self-assembly include, but are not limited to, gravity, van der Waals forces, electrostatic interactions, hydrogen bonding, hydrophobic interactions, dipole interactions.
  • the size and size of the nanoparticle aggregates and the number of nanoparticles contained in the nanoparticle aggregates can be controlled by conditions such as concentration of the nanoparticle dispersion, self-assembly time, and the like.
  • the substrate further includes a first layer composed of a first material, a second layer disposed above the first layer and composed of a second material, and a plurality of upper surfaces of the second layer are distributed Nano-depression.
  • the first material is preferably a metal or an alloy.
  • the second material is preferably a metal oxide or a non-metal oxide.
  • the first material is aluminum and the second material is aluminum oxide.
  • the first material is titanium and the second material is titanium dioxide.
  • a second aspect of the present invention also provides a SERS unit comprising: a substrate comprising a first layer composed of a first material, a second layer disposed above the first layer and composed of a second material, the The upper surface of the second layer is distributed with a plurality of nano-depressions; a plurality of nano-particle aggregates, each nano-particle aggregate is formed by aggregating a plurality of nano-particles, and each nano-particle aggregate is respectively replaced by a corresponding nano-depression limit.
  • the first material is a metal or an alloy.
  • the second material is a metal oxide or a non-metal oxide.
  • the first material is aluminum and the second material is aluminum oxide.
  • the nanoparticle aggregates have an average number of nanoparticles of 3-6.
  • the nanoparticle aggregates are formed by self-assembly of the nanoparticles in the nano-recesses.
  • the distance between two adjacent nano-recessed portions is generally not more than 100 nm, preferably not more than 50 nm, and more preferably 10 nm to 30 nm.
  • a third aspect of the invention also provides a SERS chip (also referred to as a SERS substrate) comprising one or more of the SERS units disclosed herein.
  • a fourth aspect of the invention provides a SERS detection system comprising a Raman spectrometer and a SERS chip disclosed herein.
  • the Raman spectrometer comprises a housing, a spectrometer module disposed inside the housing, and a Raman probe for detecting the housing.
  • the Raman spectrometer is used for Raman spectroscopy detection of the target to be tested placed on the SERS chip to obtain a spectral detection result.
  • the fifth aspect of the present invention also provides the use of the above-described SERS unit, SERS chip and SERS detection system comprising the same in the trace analysis of a substance or the detection of biomolecules.
  • a sixth aspect of the invention provides a method for preparing a SERS unit suitable for surface enhanced Raman detection, the preparation method comprising the steps of:
  • the nanoparticles self-assembling in the nano-depression, forming nano-atoms corresponding to the nano-depressions Particle aggregates, each nanoparticle aggregate is confined in a corresponding nano-recess.
  • the number of nanoparticles in the nanoparticle aggregates is controlled by setting a predetermined time.
  • the substrate is an alumina template or a titania template prepared by anodization.
  • the present invention has the following advantages compared with the prior art:
  • the SERS unit and the SERS chip of the invention have high SERS activity (EF ⁇ 10 8 ), high uniformity (any 1 ⁇ m 2 point error ⁇ 10%), excellent stability (> 1 year) and batch reproducibility ( The error is ⁇ 15%).
  • the invention realizes the self-assembly and controllable growth of the nanoparticles by constructing a controllable microscopic disordered nano-depression on the surface of the substrate, thereby realizing the accuracy of the morphology, size and distribution uniformity of the nanoparticle aggregates. control.
  • the invention only uses the dispersion of nanoparticles to soak the substrate for self-assembly of nanoparticles, does not require a high-cost sputtering process, is extremely convenient to operate, has controllable method, and has low preparation cost (compared with SERS prepared in the prior art)
  • the chip, the cost of the present invention is only about 10% thereof, and can realize large-area, large-scale, high-efficiency production.
  • FIG. 1 is a partially enlarged schematic view of a SERS unit in accordance with some embodiments of the present invention.
  • FIG. 2 is a schematic enlarged view of a single nano-depression and a single nanoparticle aggregate in a SERS cell in accordance with further embodiments of the present invention
  • FIG. 3 is an enlarged schematic longitudinal cross-sectional view of a SERS unit in accordance with some embodiments of the present invention.
  • 4A-4D are transmission electron microscope (TEM) images of spherical gold (Au) nanoparticles of different particle sizes in some embodiments of the invention.
  • TEM transmission electron microscope
  • 5-6 are SEM images of templates prepared by nanosphere printing and electrochemical methods in some embodiments of the present invention.
  • FIG. 7-8 are SEM images of a nanoparticle aggregate assembled by using the pore structure of the template shown in FIG. 5 and FIG. 6 according to some embodiments of the present invention.
  • 9-10 are SEM images of SERS units prepared in different soaking times in some embodiments of the present invention.
  • FIG. 11 is a schematic diagram showing changes in SERS activity of a SERS unit as a function of the number of nanoparticles in an aggregate in some embodiments of the present invention
  • Figure 13 shows the activity of 10 batches of SERS units prepared under the same preparation conditions in accordance with one embodiment of the present invention
  • SERS spectrum image obtained by detecting a plurality of probe molecules of 1 ppm using a SERS unit as an chip according to an embodiment of the present invention
  • Figure 15 is a graph showing SERS responses of different concentrations of target molecules (p-mercaptobenzoic acid, MBA) on a typical SERS unit in an embodiment of the invention.
  • target molecules p-mercaptobenzoic acid, MBA
  • the nano-recessed portions of the present invention are also referred to as nanopores or nanopores or nanopores.
  • the nano-recessed portion, the nano-pore, the nano-pore, the nano-pore, and the nano-structure referred to in the present invention means a nano-depression, a hole, a hole, and a structure having a nanometer size, and the range of the nano-size is not specifically described. 1 nm to 1000 nm.
  • Nanoparticle aggregates of the invention are also described as nanoparticle units in certain embodiments.
  • the distance between adjacent nano-recessed portions according to the present invention refers to the closest distance between adjacent two nano-recessed opening edges.
  • the mouth diameter of the present invention refers to the largest of a plurality of distances between any two points on the opening edge of the nano-recess.
  • a SERS unit 100 provided by some embodiments of the present invention, comprising: a substrate 1, a plurality of nano-pits 2 distributed on the surface of the substrate 1, and a plurality of nano-particle aggregates 3.
  • Each of the nanoparticle aggregates 3 is formed by aggregating a plurality of nanoparticles 30, and each of the nanoparticle aggregates 3 is respectively limited by a corresponding nano-pit 2 .
  • the substrate 1 has an upper surface 10, a lower surface, and side surfaces 11 located around, and a plurality of nano-pits 2 are discretely distributed on the upper surface 10 of the substrate 1.
  • the plurality of nanoparticles 30 in the nanoparticle aggregate 3 are arranged in a single layer, and the nanoparticle aggregate 3 includes a first portion located below the opening surface of the nano depressed portion 2 and a second portion located above the opening surface of the nano depressed portion 2, In the direction along the depth of the nano-recess 2, the length of the first portion is greater than the length of the second portion, and the length of the second portion does not exceed half the particle size of the nanoparticles.
  • Upper surface 10 can be flat or non-flat. In some embodiments, the upper surface 10 includes, but is not limited to, an arc, an undulating shape, or a wave shape.
  • the plurality of nano-pits 2 have a porous structure.
  • the substrate 1 can be an inorganic material, an organic material or an inorganic/organic composite material.
  • the substrate 1 includes, but is not limited to, a metal material, a metal oxide material, a semiconductor material, a polymer template, a single crystal silicon, a quartz plate, a glass piece, a polytetrafluoroethylene, and a plastic.
  • the substrate 1 comprises an alumina template.
  • the distance between adjacent nano-pits 5 of the present invention does not exceed 100 nm, preferably does not exceed 50 nm, and more preferably is 10 to 30 nm.
  • the distance between the nanoparticle aggregates 3 is controlled by the distance between the nano-pits 2 to enhance the Raman signal of the SERS unit.
  • the diameter of the mouth of the nano-recessed portion 5 of the present invention ranges from 50 nm to 1 ⁇ m, preferably from 100 nm to 500 nm, and more preferably from 100 to 400 nm.
  • the depth of the nano-recessed portion 5 of the present invention ranges from 30 nm to 300 nm, preferably from 50 nm to 200 nm, and more preferably from 60 nm to 150 nm.
  • the depth of the nano-recessed portion 2 preferably does not exceed 3 times the particle diameter of the nano-particle 30, more preferably does not exceed 2 times the particle diameter of the nano-particle 30, so that the nano-particle aggregate 3 is closer to the opening of the nano-recessed portion 2.
  • the internal shape of the nano-recess 2 includes, but is not limited to, a cylindrical shape or an inverted tapered shape.
  • the upper surface 10 of the substrate 1 per square centimeter has 10 8 to 10 10 nano-recesses 2, respectively.
  • the method of fabricating the substrate 1 includes, but is not limited to, photolithography, plasma etching, nanoimprinting, electrochemical etching, or chemical etching. Substrates are also commercially available.
  • the substrate 1 is produced from a matrix material by electrochemical anodization.
  • the electrochemical anodic oxidation method can be specifically referred to, but not limited to, Document 1: J. Am. Chem. Soc. 127, 3710; Chem. Commun. 53, 7949. 6 and 7 show SEM images of a SERS unit substrate 1 prepared by an electrochemical anodization method according to some embodiments of the present invention, each having a honeycomb structure distribution.
  • the nano-recessed portion of the surface of the SERS cell substrate shown in FIG. 6 has a diameter of about 100 nm, a depth of about 100 nm, and a distance between adjacent nano-pits 5 of about 20 nm.
  • the nano-recessed portion of the surface of the SERS cell substrate shown in FIG. 7 has a diameter of about 300 nm, a depth of about 200 nm, and a distance between adjacent nano-pits 5 of about 40 nm.
  • the number of nanoparticles 30 contained in the nanoparticle aggregates 3 of the present invention is related to the particle diameter of the nanoparticles 30 and the volume or mouth area of the nano-pits 2.
  • the number of nanoparticles 30 contained in the nanoparticle aggregate 3 is 1 to 15, preferably 2 to 10, and more preferably 3 to 6.
  • the number of nanoparticles 30 contained in the nanoparticle aggregates 3 includes, but is not limited to, two, three, four, five, six, seven, eight, nine, ten, 11 and 12.
  • the nanoparticle aggregates 3 having a difference in the number of nanoparticles contained within three are the majority, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more or 99% or more.
  • the number of nanoparticles is randomly distributed.
  • the average number of the nanoparticles 30 contained in the nanoparticle aggregate 3 is 3 to 6.
  • the number of nanoparticles in the range of 3 to 8 nanoparticle aggregates 3 accounts for more than 90%, and the number of nanoparticles in the 4 to 7 nanoparticle aggregates 3 accounts for 80%. As described above, the number of nanoparticles in the range of 5 to 6 nanoparticle aggregates 3 accounts for 50% or more. The average number of the nanoparticles 30 contained in the nanoparticle aggregate 3 is five.
  • the number of nanoparticles having 5 to 10 nanoparticle aggregates is more than 90%, and the number of nanoparticles having 6 to 9 nanoparticle aggregates is 80. More than %, the number of nanoparticles in the number of 7 to 8 nanoparticle aggregates 3 accounted for 50% or more.
  • the average number of the nanoparticles 30 contained in the nanoparticle aggregate 3 is seven.
  • the nano-recessed portion 2 has a depth of 60 nm to 120 nm, the mouth diameter ranges from 100 nm to 300 nm, and the distance between two adjacent nano-recessed portions 2 is 20 to 50 nm, and each nano-recessed portion 2 is limited to a corresponding nanoparticle aggregate 3, the nanoparticle aggregate 3 includes 3-8 nanoparticles 30, each nanoparticle 30 has a particle size ranging from 30 to 60 nm, and the number of nanoparticles is 4-7.
  • the nanoparticle aggregates 3 account for 80% or more, and the number of nanoparticles is 4 to 7 nanoparticle aggregates 3, and the number of nanoparticles is randomly distributed between 4 and 7.
  • the shape of the nanoparticles 30 is not particularly limited, and may be, for example, a regular or irregular spherical shape, a block shape, a sheet shape or a rod shape.
  • the particle diameter of the nanoparticles 30 ranges from 15 to 120 nm, preferably from 30 to 60 nm.
  • the nanoparticles 30 of the present invention comprise all nanoparticles having SERS activity.
  • the nanoparticles 30 are selected from the group consisting of nanoparticles of an alloy of one or more of gold, silver, copper, platinum, or aluminum, or any combination thereof.
  • the nanoparticles 30 are alloy structures or core-shell structures.
  • the nanoparticles 30 in the nanoparticle aggregate 3 are closely arranged or closely packed, and the gap between adjacent nanoparticles 30 in the nanoparticle aggregate 3 is 1 to 2 nm.
  • the nanoparticles 30 in the nanoparticle aggregates 3 are arranged in a single layer, as shown in FIG.
  • SERS active nanoparticles can be obtained by wet process synthesis or commercially available.
  • the synthetic process and conditions can be referred to, but not limited to, Document 2: Angew. Chem. Int. Ed. 45, 3414.
  • 4A-4D are SEM images of gold nanoparticles prepared in accordance with the present invention.
  • the size and/or shape of the nanoparticle aggregates 3 are different due to the limitation of the different nano-pits 2 and the randomness of self-assembly growth.
  • the number of nanoparticles contained in the nanoparticle aggregate 3 is generally similar, but there are random differences.
  • the nanoparticle aggregates having a difference in the number of nanoparticles within 3 are predominant, preferably 80% or more, or 90% or more, or 95% or more, or More than 99%.
  • the number of nanoparticles is randomly distributed.
  • the nanoparticles form nanoparticle aggregates 3 in the nano-depressions by self-assembly in the liquid phase.
  • the driving forces for self-assembly include, but are not limited to, gravity, van der Waals forces, electrostatic interactions, hydrogen bonding, hydrophobic interactions, dipole interactions.
  • the size and size of the nanoparticle aggregates and the number of nanoparticles contained in the nanoparticle aggregates can be controlled by conditions such as the concentration of the nanoparticle dispersion, self-assembly time, and the like.
  • the nano-pits 2 of a desired size and gap can be obtained by the structural design of the nano-pits 2, and the size, gap or shape between the nano-particle aggregates 3 can be controlled.
  • the surface of the nanoparticle and the surface of the substrate are modified, and the surface modifying group of the nanoparticle and the surface modifying group of the substrate comprising the nano-depression 2 generate self-assembly driving forces, such as opposite charges, and/or poles. sexually similar, and / or produce hydrogen bonds.
  • the size of the different nanoparticle aggregates in the SERS unit does not differ by more than the pore size of the nano-depression, and the shape and/or size of at least two nanoparticle aggregates are different, such that the nanoparticle aggregates in the SERS unit of the present invention Microscopic disorder and macroscopic uniformity.
  • researchers in the prior art have consistently sought to obtain uniform microscopic nanostructures in pursuit of repeatable SERS substrates.
  • the inventors of the present invention found that energy resonances are highly likely to occur between nano-particle aggregates with similar structures, and the energy accumulated at the gaps of the nanoparticles ("hot spots") is dissipated, resulting in "hot spots”.
  • the present invention makes a difference in the size and/or shape of the nanoparticle aggregates confined in different nano-depressions by different microscopic differences in size and/or shape of different nano-recessed portions, and the number of nanoparticles contained in the nano-particle aggregates The overall is similar, but there are random differences, showing a certain microscopic disorder. This breaks through the conventional understanding of excellent SERS substrates. On the one hand, it is possible to avoid interaction between nanoparticle aggregates of the same structure, to eliminate its adverse effect on plasma localization, and to greatly enhance the SERS activity of the SERS unit as a SERS substrate.
  • nanoparticle aggregates (about 100 or more) in a large area (1 ⁇ m 2 ) are very close in overall performance, and thus have macroscopic uniform characteristics, so that the SERS unit is very uniform. In turn, the reliability of the SERS test results can be guaranteed, so that it can be well applied to quantitative detection.
  • the nanoparticle aggregates are reduced or prevented from being displaced by liquid flow shear or other physical or chemical action during use of the SERS unit or The influence of shape and structure changes is beneficial to obtain stable and accurate detection results.
  • the nanoparticle aggregate comprises a first portion below the open face of the nano-recess and a second portion above the open face of the nano-depression, the volume of the first portion being greater than the volume of the second portion.
  • the volume of the first portion as a percentage of the volume of the nanoparticle aggregate is preferably 70% or more, and more preferably 90% or more.
  • Figure 2 discloses a schematic representation of a single nanorecess 2' and its constrained nanoparticle aggregates 3' in some embodiments of the invention.
  • the 3' portion of the nanoparticle aggregate is located above the opening of the nano-pit portion 2'.
  • the nanoparticles 30' are in a certain stacked state, but the nanoparticles 30' as a whole still belong to a single layer arrangement.
  • a SERS unit 100 has a basic structure of a SERS unit as shown in FIG. 1, and wherein the substrate 1 has a two-layer structure, specifically including a first material.
  • a layer 1a and a second layer 1b composed of a second material, the second layer 1b is located above the first layer 1a.
  • the upper surface of the second layer 1b includes a plurality of nano-pits 2.
  • the nanoparticle aggregates 3 are distributed in the nano-pits 2, and the nanoparticle aggregates 3 are in one-to-one correspondence with the nano-pits 2, and each of the nanoparticle aggregates 3 is respectively limited by a corresponding nano-recess 2 .
  • first material and the second material may independently be an inorganic material, an organic material or an inorganic/organic composite material.
  • the chemical composition of the first material and the second material are different.
  • the first material and the second material respectively include but are not limited to metal materials, metal oxide materials, semiconductor materials, polymer templates, single crystal silicon, quartz sheets, glass sheets, polytetrafluoroethylene, and plastics.
  • the first material is a metal or an alloy and the second material is a metal oxide or a non-metal oxide.
  • the first material is preferably at least one of silicon, aluminum, titanium, chromium, and copper
  • the second material is preferably at least one of silica, alumina, titania, and chromium dioxide.
  • the first material is aluminum and the second material is aluminum oxide.
  • the thickness of the second layer 1b is preferably from 30 nm to 500 nm.
  • the thickness of the first layer 1a is not particularly limited and is generally not less than 1 ⁇ m.
  • the depth of the nano-recess 2 is less than the thickness of the second layer 1b.
  • the SERS unit is preferably applied directly as a SERS chip (also known as a SERS substrate) with a maximum area of 10 cm 2 or more.
  • the SERS unit of the present invention can be used directly as a SERS substrate or a SERS chip, or can be combined with other components to form a SERS substrate or a SERS chip.
  • the invention discloses a method for preparing the foregoing SERS unit, comprising: providing a substrate having a plurality of nano-depressions distributed on a surface thereof; immersing the surface of the substrate in a dispersion containing a plurality of nanoparticles to make The nanoparticles self-assemble to form a plurality of nanoparticle aggregates, and each nanoparticle aggregate is respectively limited by a corresponding nano-recess.
  • the SERS cell preparation method of the present invention comprises first forming a porous metal oxide layer on the surface of a metal substrate by electrochemical anodization, such that the metal substrate becomes the first layer composed of metal and is made of metal.
  • a second layer of oxide forms a SERS cell substrate having a plurality of nano-pits on the surface.
  • the SERS unit substrate is immersed in a dispersion of SERS-active nanoparticles dispersed in a specific concentration, and the SERS-active nanoparticles self-assemble into a plurality of nano-depressions to form nano-aggregate-limited nanoparticle aggregates.
  • the size and size of the nanoparticle aggregates and the number of nanoparticles contained in the nanoparticle aggregates can be controlled by conditions such as the concentration of the nanoparticle dispersion, self-assembly time, and the like.
  • the preparation method may further include: controlling a time during which the surface of the substrate is immersed in the dispersion, so that each nanoparticle aggregate formed by self-assembly comprises 3 to 6 nanoparticles.
  • the preparation method of the invention has simple process and low cost, and is suitable for industrial production.
  • the SERS unit preparation method further comprises further surface modification of the surface of the SERS active nanoparticles and/or the SERS unit substrate to form a self-assembly driving force.
  • the self-assembling driving force includes, but is not limited to, at least one of gravity, van der Waals force, electrostatic action, hydrogen bonding, hydrophobic interaction, and dipole interaction.
  • the SERS active nanoparticles and/or the SERS unit substrate surface are each hydrophobically modified.
  • the SERS active nanoparticles and/or the SERS unit substrate surface are each subjected to a positive and negative electrical modification.
  • FIGS 8 and 9 disclose SEM images of SERS units in accordance with some embodiments of the present invention.
  • the SERS units shown in Figures 8 and 9 are formed from the SERS unit substrate self-assembled nanoparticle aggregates of Figures 6 and 7, respectively. It can be seen from the figure that the assembly efficiency of nanoparticle aggregates is very high, and nanoparticle aggregates are formed in almost all channels, and the structure of each aggregate is slightly different due to the different pores, which satisfies the microscopic disorder. feature. From a large scale, the number of aggregates in the same area and the number of average particles contained are very close, so they also satisfy the characteristics of macroscopic uniformity. In addition, the distance between the arrays of aggregates is short, and more sources can be collected in the same area.
  • the influence of the previously cut substrate shown in FIG. 6 on the aforementioned Au nanoparticle dispersion liquid for different time (1h, 5h) is shown for the obtained SERS unit. It can be seen that after the aforementioned substrate is immersed in the nanoparticle dispersion, the nanoparticles are continuously self-assembled into the nanopore structure of the substrate. As time goes on, the number of nanoparticles forming nanoparticle aggregates gradually increases and reaches saturation in about 10 hours. The number of nanoparticles in a saturated nanoparticle aggregate is determined by the size of the nanoparticle and the pore size.
  • the SERS unit of the embodiment of the present invention can be realized only by changing the assembly time, and thus has the characteristics of being convenient and easy to control.
  • the SERS activity of each SERS unit as a SERS substrate is varied as the number of nanoparticles in the nanoparticle aggregate changes.
  • the number of nanoparticles in the nanoparticle aggregates in the SERS unit can be achieved.
  • the number of nanoparticles contained in each nanoparticle aggregate is not more than 1, most of the nanoparticles exist in the nanopore alone, and there is no "hot spot effect", so the SERS activity of the SERS unit is low.
  • the "hot spot effect” gradually increases, and its SERS activity rapidly increases, and tends to a maximum when the average number of particles is between 4 and 5.
  • the localized plasma begins to diverge, and the electromagnetic field enhancement ability at the hot spot decreases, so the SERS activity of the SERS unit begins to decrease.
  • the structural difference between the nano-aggregates becomes smaller and smaller, and the phenomenon of "resonance" is more likely to occur, further reducing the activity of the SERS unit.
  • Fig. 12 is a picture taken by imaging analysis of the area of the SERS unit obtained in the foregoing embodiment of 4.82 mm * 4.26 mm, in which 51333 (241 * 213) data points were detected in steps of 20 ⁇ m.
  • the results show that signal fluctuations in almost all regions are within 10%, sufficient to verify good uniformity of this SERS unit.
  • the nanoparticle aggregate structure is different for each nanopore, the SERS detection will select signals from all aggregates in the tens to hundreds of square micrometers. Due to the macroscopic uniformity of the SERS unit, the SERS unit is very uniform, and the uniformity of the SERS substrate is a necessary prerequisite for reliable SERS test results and a necessary prerequisite for quantitative detection. It is in this case that the signal strength corresponds to the number of molecules tested. Otherwise, there are orders of magnitude difference in signals in different regions, and accurate test results will not be obtained.
  • the SERS unit of the embodiments of the present invention is suitable for semi-quantitative or even quantitative analysis, thanks to the aforementioned good uniformity and batch reproducibility.
  • Figure 15 shows the SERS responses of different concentrations of the target molecule (p-mercaptobenzoic acid, MBA) on this typical SERS unit. It can be seen that as the concentration of the target molecule decreases, the SERS intensity also decreases, and in a wide range, the SERS intensity and the logarithm of the concentration show a quasi-linear relationship. The above has made a strong guarantee for the quantitative detection of MBA.
  • the obtained SERS unit also has a rather excellent performance, such as high SERS activity (EF ⁇ 10 8 ), high uniformity (any 1 ⁇ m 2 point error ⁇ 10%), high stability (>1 year) and batch reproducibility (error ⁇ 15%).
  • This embodiment provides a SERS chip which is composed of one SERS unit.
  • the SERS unit has a size of 4 mm*4 mm, and the SERS unit includes a substrate having a plurality of nano-recesses distributed on the surface, and a nanoparticle aggregate dispersed in the nano-depression, each nanoparticle aggregate being composed of a plurality of nanoparticles Aggregation is formed and each nanoparticle aggregate is respectively limited by a corresponding nano-recess.
  • the SERS unit is prepared by the following steps:
  • an alumina template prepared by anodization (the alumina template is a two-layer structure, the lower layer is a metal aluminum layer of about 0.3 mm thick, the upper layer is an aluminum oxide layer of about 80 nm thick, and the SEM image of the alumina template)
  • the plurality of nano-depressions are microscopically disordered and macroscopically distributed on the entire surface of the substrate, and the number of nano-depressions per square centimeter on the substrate is about 10 8 to 10 9 , nanometer.
  • the diameter of the depressed portion is about 90 nm
  • the depth of the nano depressed portion is about 80 nm, which is slightly smaller than the thickness of the aluminum oxide layer, and the distance between the adjacent two nano-recessed portions is about 20 nm.
  • the substrate is cut to a length of 4 mm. Square piece with a width of 4mm.
  • nano gold dispersion 1 mL of a 1% aqueous solution of chloroauric acid was added to a 200 mL three-necked flask and diluted to 100 ml; a reducing agent sodium citrate solution of 1% was added under reflux with stirring to obtain a nanometer.
  • the surface of the substrate was cleaned and/or surface-treated, it was immersed in a nano gold dispersion to control the immersion time to 2 h. After 2 hours, it was taken out and air-dried to obtain a SERS unit.
  • the SEM image of the SERS unit obtained in this example is shown in Fig. 9. It can be seen that nanoparticle aggregates are formed in each nano-depression, and most of the nanoparticle aggregates contain a plurality of spherical nanoparticles aggregated together. (There are only a small number of nanoparticles in the nano-recessed portion), and the number of nanoparticles contained in each nanoparticle aggregate is 3 to 6, and the average number is about 5. The nanoparticles within each nano-depression are arranged in a single layer.
  • This embodiment provides a SERS chip which is substantially the same as Embodiment 1, except that the immersion time is controlled to be 4 h during preparation.
  • the SEM image of the SERS chip obtained in this example is shown in Fig. 10. It can be seen that nanoparticle aggregates are formed in each nano-depression, and most of the nanoparticle aggregates contain a plurality of spherical nanoparticles aggregated together. The number of nanoparticles contained in each nanoparticle aggregate is 6 to 10, and the average number is about 8. The nanoparticles within each nano-depression are arranged in a single layer.
  • the embodiment provides a SERS chip, which is substantially the same as the first embodiment.
  • the alumina template prepared by the anodization method has a nano-recessed portion having a diameter of about 500 nm and a nano-depressed portion having a depth of Around 300 nm, the distance between two adjacent nano-recessed portions is about 50 nm.
  • the SEM image of the SERS substrate obtained in this example is shown in Fig. 8. It can be seen that nanoparticle aggregates are formed in each nano-depression, and most of the nanoparticle aggregates contain a plurality of spherical nanoparticles aggregated together. The number of nanoparticles contained in each nanoparticle aggregate is 1 to 10, and most of the nano-depressions have 3-7 nanoparticles.
  • the embodiment provides a SERS chip, which is substantially the same as the first embodiment.
  • the aluminum oxide template prepared by the anodization method has a nano-depression of about 200 nm and a depth of the nano-depression. Around 150 nm, the distance between two adjacent nano-recessed portions is about 40 nm.
  • the present embodiment provides a SERS chip, which is substantially the same as Embodiment 1.
  • a silicon substrate having a plurality of nano-recessed portions on the surface is prepared by nanoimprinting, and the diameter of the nano-recessed portion is Around 500 nm, the depth of the nano-recessed portion is about 300 nm, and the distance between two adjacent nano-recessed portions is about 50 nm.
  • the embodiment provides a SERS chip including a substrate.
  • the surface of the substrate is provided with a detection area, and two SERS units as shown in Embodiment 1 are disposed in the detection area.
  • a Raman spectroscopy detection system comprising a Raman spectroscopy and a SERS chip, and the SERS chip may be the SERS chip provided in Embodiments 1 to 6.
  • the Raman spectrometer is used for performing Raman spectroscopy on a target to be measured on a SERS chip to obtain a spectrum detection result.
  • the Raman spectrometer can be any of various types of Raman spectrometers known, including but not limited to desktop Raman, portable Raman, handheld Raman, micro Raman, etc. without any limitation.
  • the desktop Raman spectrometer may specifically be a desktop Raman spectrometer such as DeltaNu's Advantage 532, Advantage 633, Advantage 785TM or the like.
  • the standard substance ethanol solution was set at a concentration of 1 ppm, and the reference materials were melamine, malachite green, Sudan red I, and hexamethyltetramine. 200 ul of the prepared solution was taken, the chip was immersed therein, taken out after ten minutes, rinsed with ethanol, and dried, followed by Raman spectroscopy. The test results are shown in Fig. 14. At a low concentration of 1 ppm, the SERS unit can clearly show the typical characteristic peaks of these substances, indicating that the SERS unit has satisfactory SERS activity, which can be used as a trace detection. The substrate has made an important guarantee.

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Abstract

一种SERS单元及其制备方法与应用，SERS单元（100）包括：表面具有离散分布的多个纳米凹陷部（2）的基材（1），多个纳米粒子聚集体（3），每一纳米粒子聚集体（3）由多个纳米粒子（30）聚集形成，且每一纳米粒子聚集体（3）分别被一对应的纳米凹陷部（2）所限制。SERS单元（100）的制备方法包括：将包含纳米粒子（30）的分散液对具有纳米凹陷部（2）的基材（1）进行浸渍，利用纳米粒子（30）自组装获得SERS单元（100）。

Description

SERS单元及其制备方法与应用 技术领域
本发明涉及表面增强拉曼(Surface-Enhanced Raman Scattering，SERS)技术，特别涉及用于表面增强拉曼检测的芯片及其制备方法与应用。
背景技术
表面增强拉曼(Surface-Enhanced Raman Scattering，SERS)是通过金属纳米结构表面上或附近的探针分子与金属表面发生等离子共振(Surface Plasmon Resonance，SPR)相互作用从而引发拉曼增强散射，SERS产生的拉曼信号较普通拉曼散射会增强10 3-10 14倍。相对于其它光谱检测方法，SERS具备高灵敏度、高选择性和检测条件宽松三个明显优势，可广泛地应用于痕量分析、单分子检测、生物医学检测、表面吸附和催化反应等诸多领域。
SERS活性的高低与SERS芯片(又称SERS基底)的结构尤其是其上的纳米结构密切相关。早期的SERS芯片，如电化学的粗糙金属电极或贵金属纳米溶胶滴干后形成的纳米粒子团聚体，由于其纳米结构具有随机性，导致SERS信号不均匀，目标分子信号重复性差，严重影响了SERS技术的发展和应用。为了获得可重复的SERS信号，人们制备了一系列具有规则纳米结构的SERS基底。例如，CN103590037A公开了一种单层膜结构的SERS基底，该SERS基底具有高度规则的纳米结构，均匀性优异，检测结果具有较高的重现性和可信度。然而，其增强因子(EF)仅有10 6，限制了其在痕量分析中的应用。还有些研究人员通过原子蒸镀、磁控溅射、脉冲沉积或电化学沉积制备纳米粒子聚集体，获得了较高的增强因子，但是制备工艺复杂，可控性差，成本高，从而很难实现规模化推广应用。
随着人类社会的发展，在食品卫生，环境污染，公共安全方面的痕量物质检测需求越来越高。而具有超高灵敏度的SERS技术(甚至可实现单分子检测)发展至今虽然已近50年，却因受限于低成本高质芯片的获得，而无法在痕量物质检测中普及应用。有鉴于此，提供一种成本低廉、制备工艺简单、高度重现且具有高SERS活性而能够广泛用于痕量分析的芯片具有重要的意义。
发明内容
本发明的目的是提供一种具有新型纳米结构的SERS芯片，以克服现有技术的不足。
为实现上述目的，本发明第一方面提供一种SERS单元，其包括：基材，其表面具有离散分布的多个纳米凹陷部；多个纳米粒子聚集体，每一纳米粒子聚集体由多个纳米粒子聚集形成，且每一纳米粒子聚集体分别被一对应的纳米凹陷部所限制。
所述离散分布指所述多个纳米凹陷部在所述的基材的表面上各自分离分布，呈微观无序而宏观均一状。纳米凹陷部包括但不限于纳米坑、纳米孔洞等形态。
根据本发明的一个方面，相邻两个所述纳米凹陷部之间的距离不超过100nm，优选不超过50nm，更优选为10nm～30nm。
在一些优选实施方式中，纳米粒子聚集体通过纳米粒子在液相中自组装方式形成。自组装的驱动力包括但不限于重力、范德华力、静电作用、氢键、疏水作用、偶极相互作用。所述纳米粒子聚集体的大小尺寸以及所述纳米粒子聚集体中所含纳米粒子的数量可通过纳米粒子分散液的浓度、自组装时间等条件来控制。
在一些优选实施方式中，所述基材进一步包括由第一材料构成的第一层、设置在第一层上方且由第二材料构成的第二层，第二层的上表面分布有多个纳米凹陷部。第一材料优选为金属或合金。第二材料优选为金属氧化物或非金属氧化物。根据一些实施例，第一材料为铝，第二材料为氧化铝。根据另一些实施例，第一材料是钛，第二材料是二氧化钛。
本发明第二方面还提供一种SERS单元，其包括：基材，其包括由第一材料构成的第一层、设置在第一层上方且由第二材料构成的第二层，所述第二层的上表面分布有多个纳米凹陷部；多个纳米粒子聚集体，每一纳米粒子聚集体由多个纳米粒子聚集形成，且每一纳米粒子聚集体分别被一对应的纳米凹陷部所限制。
根据一些实施例，所述第一材料为金属或合金。所述第二材料为金属氧化物或非金属氧化物。根据一些实施例，所述第一材料为铝，所述第二材料为氧化铝。
根据一些实施例，所述纳米粒子聚集体含有的纳米粒子的平均个数为3～6个。
优选地，所述的纳米粒子聚集体通过所述纳米粒子在所述纳米凹陷部内自组装形成。
相邻两个纳米凹陷部之间的距离一般不超过100nm，优选不超过50nm，更优选为10nm～30nm。
本发明第三方面还提供一种SERS芯片(也称SERS基底)，其包括一个或多个本发明披露的SERS单元。
本发明第四方面提供一种SERS检测系统，其包括拉曼光谱仪和本发明披露的SERS芯片。进一步地，所述拉曼光谱仪包括壳体、设置在壳体内部的光谱仪模块及探出壳体的拉曼探头。拉曼光谱仪用于对放置在SERS芯片上的待测目标进行拉曼光谱检测，得到光谱检测结果。
本发明第五方面还提供本发明上述的SERS单元、SERS芯片以及包含该SERS芯片的SERS检测系统在物质的痕量分析或生物分子的检测中的应用。
本发明第六方面提供一种适用于表面增强拉曼检测的SERS单元的制备方法，所述制备方法包括以下步骤：
提供基材，其表面包括离散分布的多个纳米凹陷部基体材料；
提供具有SERS活性的纳米粒子的分散液；
将所述基材或包括多个纳米凹陷部的基材表面浸没于所述分散液中预定时间，纳米粒子在所述纳米凹陷部中自组装，形成与所述纳米凹陷部一一对应的纳米粒子聚集体，每一纳米粒子聚集体被限制在对应的纳米凹陷部中。
根据本发明，通过设置预定时间控制纳米粒子聚集体中纳米粒子的个数。
根据本发明的一个方面，所述的基材是阳极氧化法制备的氧化铝模板或二氧化钛模板。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明的SERS单元及SERS芯片具有高SERS活性(EF～10 8)，高均匀性(任意1μm 2点误差＜10％)，极佳的稳定性(＞1年)和批次重现性(误差＜15％)等优点。本发明通过在基材表面构建可控的微观无序的纳米凹陷部，实现了纳米粒子的自组装可控生长，从而实现了对纳米粒子聚集体的形貌、大小尺寸以及分布均匀性的精确控制。本发明仅利用纳米粒子的分散液浸泡基材进行纳米粒子的自组装，无需高成本的溅射工艺，操作极其方便，方法可控，制备成本低(相比现有技术中制备同等质量的SERS芯片，本发明的成本仅为其约10％)，能实现大面积、大规模、高效率的生产。
附图说明
图1为根据本发明的一些实施例中SERS单元的局部放大结构示意图；
图2为根据本发明的另一些实施例的SERS单元中单个纳米凹陷部与单个纳米粒子聚集体的放大结构示意图；
图3为根据本发明的一些实施例中SERS单元的纵向剖面放大示意图；
图4A-图4D为本发明一些实施例中不同粒径的球形金(Au)纳米粒子的透射电子显微镜(TEM)图；
图5-图6为本发明一些实施例中利用纳米球印刷、电化学方法制备的模板的SEM图；
图7-图8为本发明一些实施例中利用图5、图6所示模板的孔道结构组装纳米粒子聚集体后的SEM图；
图9-图10为本发明一些实施例中不同浸泡时间制备的SERS单元的SEM图；
图11为本发明一些实施例中SERS单元的SERS活性随聚集体中纳米粒子数量改变而变化的示意图；
图12为本发明一实施例中SERS单元的面积为4.82mm*4.26mm的区域进行成像分析采集的图片；
图13显示了按照本发明一实施例在同样制备条件下制备的10批次SERS单元的活性；
图14为利用本发明一实施例的SERS单元作为芯片来对1ppm的多种探针分子进行检测所采集的SERS光谱图；
图15显示了发明一实施例中不同浓度的目标分子(对巯基苯甲酸，MBA)在典型SERS单元上的SERS响应图。
具体实施方式
为了更清楚地说明本发明的技术方案，下面将结合实施例和附图对本发明进行详细的介绍，显而易见地，下面描述中的实施例和附图仅仅是本发明的一部分非限制性实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明的纳米凹陷部，也被称为纳米孔洞或纳米孔道或纳米孔。本发明中涉及的纳米凹陷部、纳米孔洞、纳米孔道、纳米孔、纳米结构是指具有纳米尺寸的纳米凹陷部、孔洞、孔、 结构，所述纳米尺寸的范围没有特别说明时，指的是1nm～1000nm。本发明的纳米粒子聚集体，在某些实施方式中也被描述为纳米粒子单元。本发明所述的相邻纳米凹陷部之间的距离，指相邻两个所述纳米凹陷部开口边缘的最近距离。本发明所述的口部直径指是纳米凹陷部开口边缘上的任意两点之间的多个距离中的最大的距离。
如图1所示，其中显示了本发明一些实施例提供的SERS单元100，其包括：基材1，分布在基材1表面的多个纳米凹陷部2；以及多个纳米粒子聚集体3。每一纳米粒子聚集体3由多个纳米粒子30聚集形成，且每一纳米粒子聚集体3分别被一对应的纳米凹陷部2所限制。基材1具有上表面10、下表面以及位于四周的侧表面11，多个纳米凹陷部2离散分布在基材1的上表面10。纳米粒子聚集体3中的多个纳米粒子30呈单层排列，纳米粒子聚集体3包括位于纳米凹陷部2的开口面以下的第一部分和位于纳米凹陷部2的开口面以上的第二部分，沿纳米凹陷部2深度的方向上，第一部分的长度大于第二部分的长度，第二部分的长度不超过纳米粒子粒径的一半。上表面10可以是平整的或者非平整的。在一些实施方式中，上表面10包括但不限于弧形、起伏形或波浪形。优选地，多个纳米凹陷部2呈多孔结构。
根据本发明，基材1可以为无机材料、有机材料或者无机/有机复合材料。具体的，基材1包括但不限于金属材料、金属氧化物材料、半导体材料、高分子模板、单晶硅、石英片、玻璃片、聚四氟乙烯、塑料。在一个优选实施方式中，基材1包括氧化铝模板。
本发明的相邻纳米凹陷部5之间的距离不超过100nm，优选不超过50nm，更优选为10～30nm。通过纳米凹陷部2之间的距离控制所述纳米粒子聚集体3之间的距离，增强SERS单元的拉曼信号。本发明的纳米凹陷部5的口部直径范围为50nm～1μm，优选为100nm～500nm，更优选为100～400nm。本发明的纳米凹陷部5的深度范围为30nm～300nm，优选为50nm～200nm，更优选为60nm～150nm。纳米凹陷部2的深度优选不超过所述纳米粒子30粒径的3倍，更优选不超过所述纳米粒子30粒径的2倍，以使纳米粒子聚集体3更靠近纳米凹陷部2的开口。纳米凹陷部2的内部形状包括但不限于柱形或者倒锥形。优选地，每平方厘米的基材1的上表面10上分别具有10 8～10 10个纳米凹陷部2。
根据本发明，基材1的制作方法包括但不限于光刻法、等离子刻蚀法、纳米压印法、电化学刻蚀法或者化学刻蚀法。基材同样也可以从商业途径获取。在一个优选实施方式中，基材1由基体材料通过电化学阳极氧化法制作得到。电化学阳极氧化法具体可参考但不限于文献1：J.Am.Chem.Soc.127，3710；Chem.Commun.53，7949。图6、图7示出了本发明一些实施方式通过电化学阳极氧化方法制备SERS单元基材1的SEM图，均呈蜂窝结构分布。图6显示的SERS单元基材表面的纳米凹陷部的口径约100nm、深度约100nm、相邻纳米凹陷部5之间的距离约20nm。图7显示的SERS单元基材表面的纳米凹陷部的口径分别约300nm、深度约200nm、相邻纳米凹陷部5之间的距离约40nm。
本发明纳米粒子聚集体3含有的纳米粒子30的数量受纳米粒子30的粒径和纳米凹陷部2的体积或口部面积有关。优选地，纳米粒子聚集体3含有的纳米粒子30的数量为1～15个，优选为2～10个，更优选3～6个。在一些具体实施方式中，纳米粒子聚集体3含有的纳米粒子30的数量包括但不限于2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12 个。在同一个SERS单元中，所含纳米粒子个数差别在3个以内的纳米粒子聚集体3占绝大多数，优选80％以上，更优选90％以上，最优选95％以上或99％以上。纳米粒子个数差别在3个以内的纳米粒子聚集体3中，纳米粒子个数随机分布。优选地，纳米粒子聚集体3含有的纳米粒子30的平均个数为3～6个。
在一些优选实施方式中，同一SERS单元中，纳米粒子个数在3～8个的纳米粒子聚集体3占90％以上，纳米粒子个数在4～7个的纳米粒子聚集体3占80％以上，纳米粒子个数在5～6个的纳米粒子聚集体3占50％以上。纳米粒子聚集体3含有的纳米粒子30的平均个数为5个。
在另一些优选实施方式中，同一SERS单元中，纳米粒子个数在5～10个的纳米粒子聚集体3占90％以上，纳米粒子个数在6～9个的纳米粒子聚集体3占80％以上，纳米粒子个数在7～8个的纳米粒子聚集体3占50％以上。纳米粒子聚集体3含有的纳米粒子30的平均个数为7个。
在一些实施方式中，纳米凹陷部2的深度为60nm～120nm，口部直径范围为100nm～300nm，相邻两个所述纳米凹陷部2之间的距离为20～50nm，每个纳米凹陷部2中限制有一个对应的纳米粒子聚集体3，该纳米粒子聚集体3包括3～8个纳米粒子30，每个纳米粒子30的粒径范围为30～60nm，纳米粒子个数在4～7个的纳米粒子聚集体3占80％以上，纳米粒子个数在4～7个的纳米粒子聚集体3中，纳米粒子个数在4～7之间随机分布。
根据本发明，纳米粒子30的形状没有特别限制，例如可以呈规则或不规则的球状、块状、片状或棒状。纳米粒子30的粒径范围为15～120nm，优选为30～60nm。本发明的纳米粒子30包括具有SERS活性的所有纳米粒子。在一些实施例中，纳米粒子30选自金、银、铜、铂或铝中的一种或多种金属的合金的纳米粒子或它们的任意组合。在一些实施例中，纳米粒子30为合金结构或者核壳结构。
根据本发明，纳米粒子聚集体3中的纳米粒子30紧密排列或紧密堆积，纳米粒子聚集体3中相邻纳米粒子30之间的间隙为1～2nm。在一些具体实施例中，纳米粒子聚集体3中纳米粒子30呈单层排列，如图2所示。
前述的SERS活性纳米粒子可以通过湿法工艺合成或商业途径购买获得。合成工艺过程及条件可以参考但不限于文献2：Angew.Chem.Int.Ed.45，3414。图4A-图4D是本发明制备的金纳米粒子的SEM图。
根据本发明，在同一个SERS单元中，由于不同纳米凹陷部2的限制以及自组装生长的随机性，纳米粒子聚集体3的尺寸和/或形状均不同。纳米粒子聚集体3中所含纳米粒子个数总体相近，但存在随机的差别。例如，在一个优选实施例中，同一SERS单元中，纳米粒子个数差别在3个以内的纳米粒子聚集体3占绝大多数，优选80％以上，或90％以上，或95％以上，或99％以上。纳米粒子个数差别在3个以内的纳米粒子聚集体3中，纳米粒子个数随机分布。
在一个优选实施方式中，纳米粒子通过在液相中自组装的方式在纳米凹陷部中形成纳米粒子聚集体3。自组装的驱动力包括但不限于重力、范德华力、静电作用、氢键、疏水作用、 偶极相互作用。纳米粒子聚集体的大小尺寸以及所述纳米粒子聚集体中所含纳米粒子的数量可通过纳米粒子分散液的浓度、自组装时间等条件来控制。通过纳米凹陷部2的结构设计可以获得期望尺寸和间隙的纳米凹陷部2，进而可以控制纳米粒子聚集体3之间的尺寸、间隙或形状。优选地，纳米粒子表面和基材表面是经过修饰处理的，纳米粒子表面修饰基团与包括纳米凹陷部2的基材表面修饰基团产生自组装驱动力，例如带相反电荷、和/或极性相似、和/或产生氢键。
根据本发明，SERS单元中不同纳米粒子聚集体的尺寸相差不超过纳米凹陷部的孔径，且至少两个纳米粒子聚集体的形状和/或尺寸不同，使得本发明的SERS单元中纳米粒子聚集体呈微观无序而宏观均一态。现有技术的研究者在追求可重复的SERS基底时，一贯致力于获得均一的微观纳米结构。本案发明人在长期研究和大量实践中发现，结构相似的纳米粒子聚集体之间极易发生能量共振，将聚集在纳米粒子间隙处(“热点”)的能量发散出去，导致“热点”处的SERS活性大大下降。本发明通过不同纳米凹陷部的尺寸和/或形状微观差异，使得被限制于不同纳米凹陷部中的纳米粒子聚集体的尺寸和/或形状产生差异，纳米粒子聚集体中所含纳米粒子个数总体相近，但存在随机的差别，呈一定的微观无序态。这突破了人们对优秀SERS基底的常规认识。一方面，可以避免因相同结构的纳米粒子聚集体之间产生相互作用，消除其对于等离子体局域化的不利影响，大幅增强SERS单元作为SERS基底应用时的SERS活性。另一方面，从统计角度，大面积范围内(1μm 2)的纳米粒子聚集体(约100个或更多)总体性能却十分接近，因而具有宏观均一的特征，使得所述SERS单元十分均匀，进而可以保障SERS测试结果的可靠性，使之可以很好的应用于定量检测。此外，通过将各纳米粒子聚集体限制于与之相应的纳米凹陷部中，减少或避免纳米粒子聚集体在SERS单元使用的过程中受到液流剪切力或者其它物理、化学作用下发生位移或者形状、结构改变的影响，进而有利于获得稳定、准确的检测结果。在一些实施例中，纳米粒子聚集体包括位于纳米凹陷部的开口面以下的第一部分和位于纳米凹陷部的开口面以上的第二部分，第一部分的体积大于第二部分的体积。第一部分的体积占纳米粒子聚集体体积的百分数优选为70％以上，更优选为90％以上。
图2公开了本发明一些实施方式中单个纳米凹陷部2’及其限制的纳米粒子聚集体3’的示意图。其中，纳米粒子聚集体3’部分位于纳米凹陷部2’的开口以上。纳米粒子30’呈一定的堆积状态，但整体上纳米粒子30’仍属于单层排列。
如图3所示，本发明一些实施例提供的SERS单元100，其具有如图1所示的SERS单元的基本结构，且其中基材1为双层结构，具体包括由第一材料构成的第一层1a和由第二材料构成的第二层1b，第二层1b位于第一层1a之上。第二层1b的上表面包括多个纳米凹陷部2。纳米粒子聚集体3分布在纳米凹陷部2内，且纳米粒子聚集体3与纳米凹陷部2一一对应，每一纳米粒子聚集体3分别被一对应的纳米凹陷部2所限制。
进一步地，所述第一材料、第二材料可以独立地为无机材料、有机材料或者无机/有机复合材料。第一材料与第二材料的化学成分不同。具体的，第一材料、第二材料分别包括但不限于金属材料、金属氧化物材料、半导体材料、高分子模板、单晶硅、石英片、玻璃片、 聚四氟乙烯、塑料。在一个优选实施方式中，第一材料为金属或合金，第二材料为金属氧化物或非金属氧化物。在一个具体实施方式中，第一材料优选为硅、铝、钛、铬、铜中的至少一种，第二材料优选为二氧化硅、氧化铝、二氧化钛、二氧化铬中的至少一种。在一个优选实施方式中，第一材料为铝，第二材料为氧化铝。
所述第二层1b的厚度优选为30nm～500nm。第一层1a的厚度没有特别限制，一般为不小于1μm。
根据本发明的一个具体方面，纳米凹陷部2的深度小于所述第二层1b的厚度。
根据本发明，所述SERS单元优选直接作为SERS芯片(也称SERS基底)应用，其最大面积在10cm 2以上。
本发明的SERS单元可直接作为SERS基底或SERS芯片使用，也可以与其它元件配合形成SERS基底或SERS芯片。
本发明公开了一种制备前述SERS单元的方法，包括：提供表面分布有多个纳米凹陷部的基材；将所述基材表面浸没于包含多个纳米粒子的分散液中，使其中的多个纳米粒子自组装形成多个纳米粒子聚集体，且使每一纳米粒子聚集体分别被一对应的纳米凹陷部所限制。
在一些实施例中，本发明的SERS单元制备方法包括：首先通过电化学阳极氧化法在金属基材表面制作多孔的金属氧化物层，使得金属基材成为由金属构成的第一层和由金属氧化物构成的第二层，从而形成表面具有多个纳米凹陷部的SERS单元基材。其次将SERS单元基材浸入分散有特定浓度的SERS活性纳米粒子的分散液中，SERS活性纳米粒子自组装到多个纳米凹陷部中，形成纳米凹陷部限制的纳米粒子聚集体。纳米粒子聚集体的大小尺寸以及所述纳米粒子聚集体中所含纳米粒子的数量可通过纳米粒子分散液的浓度、自组装时间等条件来控制。优选地，所述的制备方法还可包括：控制将所述基材表面于所述分散液中浸泡的时间，使自组装形成的每一纳米粒子聚集体包含3～6个纳米粒子。本发明的制备方法工艺简单、成本低廉，适合产业化生产。
优选地，SERS单元制备方法还包括对SERS活性纳米粒子和/或SERS单元基材表面进一步的表面修饰，以形成自组装驱动力。自组装的驱动力包括但不限于重力、范德华力、静电作用、氢键、疏水作用、偶极相互作用中的至少一种作用力。在一些具体实施方式中，对SERS活性纳米粒子和/或SERS单元基材表面分别进行疏水性修饰。在一些具体实施方式中，对SERS活性纳米粒子和/或SERS单元基材表面分别进行正负电修饰。
图8、图9公开本发明一些实施例的SERS单元的SEM图。图8和图9所示的SERS单元分别为图6和图7的SERS单元基材自组装纳米粒子聚集体形成。由图可以看出，纳米粒子聚集体组装效率很高，几乎所有孔道内均有纳米粒子聚集体形成，并由于孔道不尽相同，每个聚集体的结构也略有差异，满足微观无序的特征。从大范围看，相同面积内的聚集体数目及包含的平均粒子个数十分接近，因此也满足宏观均一的特点。此外，聚集体阵列之间距离短，相同面积内可以收集更多的信号源。
再请参阅图10、图11，其中示出了将前述裁剪的图6所示基材于前述Au纳米粒子分散液中浸泡不同时间(1h、5h)，对于所获SERS单元的影响。可以看到，当将前述基材浸入 纳米粒子分散液后，纳米粒子不断自组装到基材的纳米孔洞结构中。随着时间延长，形成纳米粒子聚集体的纳米粒子数目逐渐增多，并在10小时左右达到饱和。饱和纳米粒子聚集体中纳米粒子数目由纳米粒子尺寸及孔道尺寸共同决定。在本实施例中，浸泡1h后，多个纳米粒子聚集体平均包含的纳米粒子个数约为5个，组装约5h后，多个纳米粒子聚集体平均包含的纳米粒子个数约为8个。相比现有SERS基底需通过改变孔径结构来调节粒子数目的方式，本发明实施例的前述SERS单元仅需改变组装时间即可实现，因此具有便捷易控的特性。
进一步地，再请参阅图11，前述实施例中，各SERS单元作为SERS基底应用时的SERS活性随纳米粒子聚集体中纳米粒子的个数变化而变化。通过控制具有纳米凹陷部的基材在纳米粒子溶液中的浸渍时间，可实现SERS单元中的纳米粒子聚集体中纳米粒子的个数。当各纳米粒子聚集体中所含纳米粒子数不大于1时，大部分的纳米粒子单独存在于纳米孔洞中，没有“热点效应”，因此SERS单元的SERS活性较低。随着各纳米粒子聚集体中的纳米粒子数增多，“热点效应”逐渐增强，其SERS活性迅速提高，并在平均粒子数为4到5之间时趋于最大值。当进一步增加粒子数，局域等离子体开始发散，其热点处的电磁场增强能力下降，因此SERS单元的SERS活性开始降低。并且，随着纳米粒子数的增多，纳米聚集体之间的结构差异越来越小，更容易发生“共振”现象，进一步降低SERS单元的活性。
图12是对前述实施例所获SERS单元的面积为4.82mm*4.26mm的区域进行成像分析采集的图片，其中以20μm为步长，共检测了51333个(241*213)数据点。结果显示几乎所有区域的信号波动在10％以内，足以验证此SERS单元良好的均匀性。虽然对于每个纳米孔洞来说，其中的纳米粒子聚集体结构不尽相同，但SERS检测将选取数十至数百平方微米内所有聚集体的信号。由于SERS单元的宏观均一特征，此SERS单元十分均匀，而SERS基底的均匀性是SERS测试结果可靠的必要前提，也是定量检测的必要前提。正是在此种情况下，才能将信号强度与所测分子数量对应。否则，不同区域信号有数量级的差别，将无法获得准确的测试结果。
再请参阅图13，其显示了利用本发明前述实施例在同样制备条件下制备的10批相同结构的SERS单元直接应用为SERS基底时的活性变化图。由图可知，不同批次SERS单元活性差异在15％之内，批次稳定性高，符合SERS基底的商业流通需求。
又请参阅图14，其显示了浓度为1ppm的几种探针分子在本发明前述实施例所获的典型SERS单元上的SERS光谱。在1ppm的低浓度下，该SERS单元仍能清晰显示这几种物质的典型特征峰，说明该SERS单元具有令人满意的SERS活性，为其能作为痕量检测基底做出了重要保证。
得益于前述的良好的均匀性和批次重现性，本发明实施例的该SERS单元适合用于半定量甚至定量分析。图15展示了不同浓度的目标分子(对巯基苯甲酸，MBA)在该典型SERS单元上的SERS响应。可以看出，随着目标分子浓度的下降，其SERS强度也呈下降趋势，并在较宽的范围内，SERS强度与浓度的对数呈现准线性关系。以上为实现MBA的定量检测做出了有力保证。
另外，若以Ag、Pt、Cu、Al等中的任一种或两种以上的组合或其与Au的组合(例如 以合金等形式组合)构成的纳米粒子(粒径为15～110nm，优选为50～60nm)替代前述的Au纳米粒子，获得的SERS单元也具有相当优异的表现，例如高SERS活性(EF～10 8)，高均匀性(任意1μm2点误差＜10％)，高稳定性(＞1年)和批次重现性(误差＜15％)等。
以下结合具体的实施例，对本发明做进一步详细的说明。实施例中未有特别说明的原料均通过商购获得。没有特别提及温度的操作在室温下进行。未有特别说明的操作方法与条件可采用本领域的公知或常规的手段与条件。
实施例1
本实施例提供一种SERS芯片，其由一个SERS单元构成。SERS单元的尺寸为4mm*4mm，该SERS单元包括表面具有离散分布的多个纳米凹陷部的基材、以及分散在纳米凹陷部内的纳米粒子聚集体，每一纳米粒子聚集体由多个纳米粒子聚集形成，且每一纳米粒子聚集体分别被一对应的纳米凹陷部所限制。
SERS单元通过以下步骤制备：
提供基材：取阳极氧化法制备的氧化铝模板(该氧化铝模板为双层结构，下层为约0.3mm厚的金属铝层，上层为约80nm厚的氧化铝层，氧化铝模板的SEM图如图6所示，多个纳米凹陷部微观无序而宏观均一地分布在基板的整个表面上，该基材上每平方厘米上的纳米凹陷部的数量约为10 8～10 9个，纳米凹陷部的口径为90nm左右，纳米凹陷部的深度为80nm左右，略小于氧化铝层的厚度，相邻二个纳米凹陷部之间的距离为约20nm左右)作为基板，裁切为长4mm、宽4mm的方形片状。
制备纳米金分散液：于200mL三颈烧瓶中加入质量浓度为1％的氯金酸水溶液1mL并稀释到100ml；在加热回流和搅拌下加入浓度为1％的还原剂柠檬酸钠溶液，获得纳米金分散液，经测试金纳米粒子的粒径为约40nm。
将基材表面清洗和/或进行表面处理后，浸入纳米金分散液中，控制浸渍时间为2h，2h后，取出，晾干，得到SERS单元。
本例得到的SERS单元的SEM图如图9所示，从中可见，在各纳米凹陷部内均形成了纳米粒子聚集体，绝大多数的纳米粒子聚集体均含有多个聚集在一起的球形纳米粒子(只有极少的纳米凹陷部内纳米粒子的数量是一个)，各纳米粒子聚集体含有的纳米粒子数为3～6个，平均数为约5个。每个纳米凹陷部内的纳米粒子基本呈单层排布。
实施例2
本实施例提供一种SERS芯片，其基本同实施例1，不同处仅在于制备时控制浸渍时间为4h。本例得到的SERS芯片的SEM图如图10所示，从中可见，在各纳米凹陷部内均形成了纳米粒子聚集体，绝大多数的纳米粒子聚集体均含有多个聚集在一起的球形纳米粒子，各纳米粒子聚集体含有的纳米粒子数为6～10个，平均数为约8个。每个纳米凹陷部内的纳米粒子基本呈单层排布。
实施例3
本实施例提供一种SERS芯片，其基本同实施例1，与实施例1不同的是，采用阳极氧化法制备的氧化铝模板，其纳米凹陷部的口径为500nm左右，纳米凹陷部的深度为300nm 左右，相邻二个纳米凹陷部之间的距离约为50nm左右。
本例得到的SERS基底的SEM图如图8所示，从中可见，在各纳米凹陷部内均形成了纳米粒子聚集体，绝大多数的纳米粒子聚集体均含有多个聚集在一起的球形纳米粒子，各纳米粒子聚集体含有的纳米粒子数为1～10个，大部分的纳米凹陷部内具有3-7个纳米粒子。
实施例4
本实施例提供一种SERS芯片，其基本同实施例1，与实施例1不同的是，采用阳极氧化法制备的氧化铝模板，其纳米凹陷部的口径为200nm左右，纳米凹陷部的深度为150nm左右，相邻二个纳米凹陷部之间的距离约为40nm左右。
实施例5
本实施例提供一种SERS芯片，其基本同实施例1，与实施例1不同的是，采用纳米压印法制备表面具有多个纳米凹陷部的硅材质基材，其纳米凹陷部的口径为500nm左右，纳米凹陷部的深度为300nm左右，相邻二个纳米凹陷部之间的距离为约50nm左右。
实施例6
本实施例提供一种SERS芯片，其包括基板，基板表面设置有检测区域，检测区域中设置有2个如实施例1所示的SERS单元。
实施例7
本实施例，提供了一种拉曼光谱检测系统，所述测试系统包括拉曼光谱仪和SERS芯片，所述SERS芯片可以是实施例1～6所提供的SERS芯片。所述拉曼光谱仪用于对位于SERS芯片上的待测目标进行拉曼光谱检测，得到光谱检测结果。
拉曼光谱仪可以是已知的各种类型的拉曼光谱仪，包括但不限于台式拉曼、便携式拉曼、手持式拉曼、微拉曼等，没有任何限制。台式拉曼光谱仪具体可以是例如DeltaNu公司的Advantage 532、Advantage 633、Advantage 785TM等型号的台式拉曼光谱仪。
SERS基底的性能测试
对实施例1的SERS芯片的性能进行测试，过程如下：
分别配置浓度为1ppm的标准物质乙醇溶液，标准物质分别为三聚氰胺、孔雀石绿、苏丹红I、六甲基四胺。取200ul配制的溶液，将芯片浸泡其中，十分钟后取出，乙醇冲洗后晾干，随后进行拉曼光谱测试。测试结果如图14所示，在1ppm的低浓度下，该SERS单元仍能清晰显示这几种物质的典型特征峰，说明该SERS单元具有令人满意的SERS活性，为其能作为痕量检测基底做出了重要保证。
需要说明的是，以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (25)

  1. 一种SERS单元，其特征在于包括：
    基材，其表面具有离散分布的多个纳米凹陷部；
    多个纳米粒子聚集体，每一纳米粒子聚集体由多个纳米粒子聚集形成，且每一纳米粒子聚集体分别被一对应的纳米凹陷部所限制。
  2. 根据权利要求1所述的SERS单元，其特征在于：相邻两个所述纳米凹陷部之间的距离不超过100nm，优选不超过50nm，更优选为10nm～30nm。
  3. 根据权利要求1所述的SERS单元，其特征在于：所述纳米凹陷部的深度为30nm～150nm。
  4. 根据权利要求1或3所述的SERS单元，其特征在于：所述纳米凹陷部的口部直径范围为50nm～1000nm，优选为100nm～300nm。
  5. 根据权利要求1所述的SERS单元，其特征在于：所述纳米粒子聚集体含有的纳米粒子数为2～10个，优选3～6个，平均纳米粒子数优选为3～6个。
  6. 根据权利要求1所述的SERS单元，其特征在于：所述纳米粒子的粒径范围为15～120nm，优选为30～60nm。
  7. 根据权利要求1所述的SERS单元，其特征在于：所述纳米粒子是选自金、银、铜、铂或铝中的一种或多种金属的合金的纳米粒子或它们的任意组合。
  8. 根据权利要求1所述的SERS单元，其特征在于：所述的纳米粒子聚集体通过纳米粒子自组装形成。
  9. 根据权利要求1所述的SERS单元，其特征在于：所述的纳米粒子聚集体中的纳米粒子紧密排列或紧密堆积，所述纳米粒子聚集体中相邻纳米粒子之间的间隙为1～2nm。
  10. 根据权利要求1所述的SERS单元，其特征在于：所述纳米粒子聚集体中，所述纳米粒子单层排列或多层排列。
  11. 根据权利要求1所述的SERS单元，其特征在于：至少两个所述纳米粒子聚集体的尺寸和/或形状不同。
  12. 根据权利要求1所述的SERS单元，其特征在于：所述纳米粒子聚集体包括位于所述纳米凹陷部的开口面以下的第一部分和位于所述纳米凹陷部的开口面以上的第二部分，所述第一部分的体积大于所述第二部分的体积。
  13. 根据权利要求1所述的SERS单元，其特征在于：每平方厘米的所述基材表面上分别具有10 8～10 10个所述的纳米凹陷部。
  14. 根据权利要求1所述的SERS单元，其特征在于：所述基材包括由第一材料构成的第一层、设置在所述第一层上方且由第二材料构成的第二层，所述第二层的上表面分布有所述多个纳米凹陷部。
  15. 根据权利要求14所述的SERS单元，其特征在于：所述第一材料为金属或者合金；和/或所述第二材料为金属氧化物或者非金属氧化物。
  16. 根据权利要求14所述的SERS单元，其特征在于：所述第一材料为硅、铝、钛、铬、铜中的至少一种；和/或，所述第二材料为二氧化硅、氧化铝、二氧化钛、二氧化铬中的至少一种。
  17. 根据权利要求14所述的SERS单元，其特征在于：所述第一材料为铝，所述第二材料为氧化铝；或者，所述第一材料为钛，所述第二材料为二氧化钛。
  18. 根据权利要求14所述的SERS单元，其特征在于：所述第二层的厚度为30nm～500nm。
  19. 一种SERS芯片，其特征在于：包括一个或者多个如权利要求1-18中任一项所述的SERS单元。
  20. 一种SERS检测系统，其特征在于：包括拉曼光谱仪和权利要求19所述的SERS芯片。
  21. 一种如权利要求1-18中任一项权利要求所述的SERS单元、如权利要求19所述SERS芯片或如权利要求20所述的SERS检测系统在物质的痕量分析或生物分子的检测中的应用。
  22. 一种如权利要求1至18中任一项权利要求所述的SERS单元的制备方法，其特征在于，包括以下步骤：
    提供基材，其表面包括离散分布的多个纳米凹陷部；
    提供SERS活性纳米粒子的分散液；
    将所述基材表面浸没于所述分散液中预定时间，纳米粒子在所述纳米凹陷部中自组装，形成与所述纳米凹陷部一一对应的纳米粒子聚集体，每一纳米粒子聚集体被限制在对应的纳米凹陷部中。
  23. 根据权利要求22所述的SERS单元的制备方法，其特征在于：通过设置预定时间控制纳米粒子聚集体中纳米粒子的个数。
  24. 根据权利要求22所述的SERS单元的制备方法，其特征在于：所述基材表面的纳米凹陷部通过纳米压印、光刻或者电化学刻蚀形成。
  25. 根据权利要求22所述的SERS单元的制备方法，其特征在于：所述的基材是阳极氧化法制备的氧化铝模板或二氧化钛模板。
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