CN106918578A - Sensor chip - Google Patents
Sensor chip Download PDFInfo
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- CN106918578A CN106918578A CN201510981843.9A CN201510981843A CN106918578A CN 106918578 A CN106918578 A CN 106918578A CN 201510981843 A CN201510981843 A CN 201510981843A CN 106918578 A CN106918578 A CN 106918578A
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- metal nano
- sensor chip
- substrate
- nano structure
- decorative layer
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Classifications
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- 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
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
- G01N21/553—Attenuated total reflection and using surface plasmons
- G01N21/554—Attenuated total reflection and using surface plasmons detecting the surface plasmon resonance of nanostructured metals, e.g. localised surface plasmon resonance
-
- 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
-
- 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
-
- 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
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N2021/258—Surface plasmon spectroscopy, e.g. micro- or nanoparticles in suspension
Abstract
The present invention discloses a kind of sensor chip, and it includes substrate, multiple metal Nano structures, first surface decorative layer and second surface decorative layer.Metal Nano structure is located on substrate.First surface decorative layer is located on the surface of metal Nano structure, and wherein first surface decorative layer includes multiple molecules with mercapto.Second surface decorative layer is located on the surface of substrate, and second surface decorative layer includes multiple molecules with silylation.Sensor chip of the invention has high sensitivity and has high linearity for the concentration of testing molecule.
Description
Technical field
The present invention relates to a kind of chip, and more particularly to a kind of sensor chip.
Background technology
Localized surface plasma resonance (Localized Surface Plasmon Resonance, LSPR)
Technology is a kind of detection mode for exempting from fluorescence calibration.In addition to the flow that can shorten detection and time, also not
Can occur because solid space obstacle and caused by the difficult problem of secondary antibodies (containing fluorescence molecule) grafting.But
The sensitivity of current LSPR chips is compared with traditional ELISA method, and sensitivity is relatively low.Main cause is removed
Can plasma resonance optical spectrum be wider outer, the sensing on metal Nano structure is close to for testing molecule
Focus (hot spot) position is also a big emphasis to produce effective spectral displacement.Therefore, how to make to treat
Survey thing to be effectively grafted on metal Nano structure, be the current researcher problem suddenly to be solved.
The content of the invention
It is an object of the invention to provide a kind of sensor chip, it has high sensitivity and for be measured point
The concentration of son has high linearity.
It is that, up to above-mentioned purpose, the present invention provides a kind of sensor chip, it includes substrate, multiple metal nanos
Structure, first surface decorative layer and second surface decorative layer.Metal Nano structure is located on substrate.The
One finishing coat is located on the surface of metal Nano structure, and wherein first surface decorative layer includes multiple tools
There is the molecule of mercapto.Second surface decorative layer is located on the surface of substrate, and second surface decorative layer includes
Molecule of the multiple with silylation.
Based on above-mentioned, due to sensor chip of the invention metal Nano structure and substrate between at a distance of one away from
From so that sensing focus is heightened by substrate and makes sensing focus exposed, therefore with sensitivity higher.
Additionally, sensor chip of the invention is by two stage surface modification, therefore except determinand can be increased
The probability of effective sensing area is grafted on, is also reduced because determinand adhesion is in the noise caused by non-sensing area
Interference, and then it is lifted at the spirit sensed with the linear relationship of signal and raising under different testing molecule concentration
Sensitivity.
It is that features described above of the invention and advantage can be become apparent, special embodiment below, and coordinate
Appended accompanying drawing is described in detail below.
Brief description of the drawings
Figure 1A to Fig. 1 F is the Making programme section of the sensor chip depicted in the first embodiment of the present invention
Schematic diagram；
Fig. 2A to Fig. 2 C is that the Making programme of the sensor chip depicted in the second embodiment of the present invention is cutd open
Face schematic diagram；
Fig. 3 is the schematic diagram of characteristic spectrum of the sensor chip of embodiment 1 in air and water；
Fig. 4 is the schematic diagram of characteristic spectrum of the sensor chip of comparative example 1 in air and water；
The schematic diagram of the FDTD analog results that Fig. 5 A are distributed for the energy hotspot of embodiment 1；
The schematic diagram of the FDTD analog results that Fig. 5 B are distributed for the energy hotspot of comparative example 1；
Fig. 6 is the comparing figure of sensitivity experiment and FDTD analog results；
Fig. 7 is the graph of a relation of the testing molecule concentration red displacement of character pair spectrum of embodiment 2；
Fig. 8 is the graph of a relation of the testing molecule concentration red displacement of character pair spectrum of comparative example 2；
Fig. 9 A are the schematic diagram of the atomic force micrograph of embodiment 2；
Fig. 9 B are the schematic diagram of the atomic force micrograph of comparative example 2.
Symbol description
10、20：Sensor chip
100、100a、300、400：Substrate
110：Photoresist layer
111：The photoresist layer of patterning
120：The mask layer of patterning
122、144：Opening
130、132：Stacked structure
140：Metal material layer
142、302、402：Metal Nano structure
142a：Upper surface
142b：Lower surface
142c：Corner regions
150、160、250、260：Finishing coat
152、252：Molecule with mercapto
162、262：Molecule with silylation
202：Supporting construction
204：Contact surface
304、404：Sensing focus
L1：The size of metal Nano structure
L2：The width of contact surface
H1：The height of metal Nano structure
H2：The height of supporting construction
P：Cycle
Specific embodiment
Figure 1A to Fig. 1 G is according to the making stream of the sensor chip depicted in the first embodiment of the present invention
Journey generalized section.First, there is provided substrate 100, substrate 100 is, for example, glass substrate.Substrate 100
On have been formed with covering for photoresist layer 110 and the patterning in this photoresist layer 110
Mold layer 120.In the present embodiment, photoresist layer 110 is organic photoresist layer, and pattern
The mask layer 120 of change is the inorganic photoresist layer of patterning.Form the mask layer 120 of patterning
Method is, for example, that inorganic photoresist layer is formed in photoresist layer 110, and blue light is then passed through again
LASER HEAT photoetching (blue ray laser thermal lithography) manufacture craft makes inorganic photoresist
Phase change is produced, thus by inorganic photoresist pattern layers.The mask layer 120 of patterning has many
Individual opening 122, the opening 122 exposes the photoresist layer 110 of part.In the present embodiment,
122 exposed regions of opening are the presumptive areas for defining metal Nano structure.
Then, Figure 1B is refer to, the mask layer 120 using patterning is etched as etching mask
Manufacture craft, removes the part photoresist layers 110 that are exposed of opening 122, with formed it is multiple that
This stacked structure 130 for separating.Etching process can for isotropic dry etch manufacture craft or it is each to
Different in nature dry ecthing manufacture craft.Isotropic dry etch manufacture craft is, for example, reactive ion etch
(Reactive Ion Etching,RIE).Anisotropic dry etch manufacture craft is, for example, inductive coupling type etc.
Plasma (Inductively Coupled Plasma etching, ICP) stacked structure 130 includes figure
The mask layer 120 of the photoresist layer 111 of case and patterning thereon.In this step, pattern
The pattern of the mask layer 120 of change is transferred to the photoresist layer 111 of patterning, that is to say, that pattern
The pattern position of the photoresist layer 111 of change is generally corresponding to the mask layer 120 of patterning.
Then, Fig. 1 C are refer to, it is on the substrate 100 between adjacent stacks structure 130 and each
Metal material layer 140, wherein stacked structure 130 and metal material thereon are formed on individual stacked structure 130
The bed of material 140 constitutes stacked structure 132.The method for forming metal material layer 140 is, for example, electron beam evaporation plating
Method (e-beam evaporation).The material of metal material layer 140 be, for example, silver, gold, platinum, copper,
Aluminium or its combination, but the invention is not restricted to this.The thickness of metal material layer 140 is, for example, 10nm to 100
nm.According to the present embodiment, due to the enough height of the height of photoresist layer 111 and mask layer 120
(<140nm), therefore when metal material layer 140 is formed, deposition metal material on the substrate 100
Layer 140 is separated with the metal material layer 140 being deposited on mask layer 120.
Afterwards, each stacked structure 132 on substrate 100 is removed.Remove the side of stacked structure 132
Method include carry out wet type divest method, dry type divest method or its combination.For thinner, by Wet-type etching or
Be dry etching method to remove while photoresist layer 111, can simultaneously will be positioned at photoresist layer
Mask layer 120 and metal material layer 140 on 111 are divested.Then, as shown in figure iD, then enter
Row heat tempering manufacture craft, to cause that the metal material layer 140 on substrate 100 forms multiple metal nanos
Structure 142.According to the present embodiment, there is opening 144 between adjacent metal nanostructured 142, it is described
Opening 144 exposes the substrate 100 of part.The size L1 of metal Nano structure 142 be, for example, between
10nm to 900nm.The height H1 of metal Nano structure 142 is, for example, between 10nm to 100nm.
In the present embodiment, as shown in Fig. 1 C and Fig. 1 D, the opening of the mask layer 120 of patterning
122 are distributed by periodically and in the way of systematicness.Therefore the position of each opening 122 corresponds to respectively
Each metal Nano structure 142.That is, those metal Nano structures 142 with periodically and
Systematicness is arranged on substrate 100, and the position pattern of its arrangement correspond to above-mentioned opening 122.Those
The cycle P of metal Nano structure 142 is, for example, between 15nm to 1000nm, wherein P>L1.Week
The structure of phase property arrangement has the advantages that high evenness, and signal will not be influenceed because of the change of measurement position
Intensity.Additionally, in the present embodiment, metal Nano structure 142 is shaped as dome-type (such as Fig. 1 D
It is shown).In another embodiment, or cylindrical type, disc type, moth ocular form, triangle column type or on
The combination stated, but the invention is not restricted to this, the usual skill in this area can change metal and receive according to its demand
The shape of rice structure.
Then, Fig. 1 E are refer to, finishing coat 150 are formed on the surface of metal Nano structure 142,
Be used to catch testing molecule (such as virus, antigen or protein) corresponding antibody (antibody) or
Aptamer (aptamer).Finishing coat 150 includes the molecule with multiple mercaptos (- SH)
152.Molecule 152 with mercapto is, for example, 11- Mercaptoundecanoic acids (11-mercaptoundecanoic
Acid, 11-MUA), 11- sulfydryls undecylamine (11-Amino-1-undecanethiol, 11-AUT), half Guang
Amine (Cysteamine), 4- aminothiophenols (4-Aminothiophenol), 4- methylbenzene phenyl-sulfhydrates
(4-Methylthiophenol), Thiolation aptamer (thiolated aptamer) or its combination.Shape
Method into finishing coat 150 is, for example, that the overall structure shown in Fig. 1 D is dipped into above-claimed cpd
Solution in.During immersion, one end mercapto of the molecule 152 with mercapto is received with metal
The metal on the surface of rice structure 142 produces reaction to form covalent bond.
Although scheming it can be seen that finishing coat 150 is contacted with the substrate 100 of part in fig. ie
The merely illustrative use of 1E, in the present embodiment, because the molecule 152 with mercapto only can be anti-with metal
Without being reacted with substrate 100, therefore only should can form surface on the surface of metal Nano structure 142
Decorative layer 150, can't form finishing coat 150 on the surface of substrate 100.Depicted in Fig. 1 E
Finishing coat 150 be schematic diagram, due to that will not produce between finishing coat 150 and substrate 100
Reaction, thus the molecule of finishing coat 150 will not actually be formed in the surface of substrate 100.
Additionally, in the present embodiment, the corresponding antibody of testing molecule or aptamer can effectively with surface
Decorative layer 150 is grafted (conjugation), therefore can improve testing molecule and fixed (immobilized)
In the probability of effective sensing area, and then lift the sensitivity of chip senses.
Thereafter, Fig. 1 F be refer to, on the surface of substrate 100 formed finishing coat 160, be used to
Anti- testing molecule is sticky.Finishing coat 160 includes the molecule 162 with multiple silylation.With silicon
The molecule 162 of alkyl such as diethanol silane (Poly (ethylene glycol)-silane, PEG-silane),
Polyvinylpyrrolidone silane (Polyvinylpyrrolidone-silane, PVP-silane), polyethylene glycol oxide
Silane (Polyethyleneoxide-silane, PEO-silane) or its combination.Form finishing coat 160
Method be, for example, that the overall structure shown in Fig. 1 E is dipped in the solution of above-claimed cpd.In immersion
During, the silylation of the molecule 162 with silylation is produced with the silica on the surface of substrate 100
It is raw to react to form covalent bond.So far, that is, the making of sensor chip 10 is completed.
In the present embodiment, due to the molecule 162 with silylation only can with substrate 100 react without
With metal Nano structure schwartzman reaction, therefore only finishing coat can be formed on the surface of substrate 100
160, finishing coat 160 can't be formed on the surface of metal Nano structure 142.Similarly, scheme
Finishing coat 160 depicted in 1F is schematic diagram, finishing coat 160 and metal Nano structure 142
Between due to reaction will not be produced, thus the molecule of finishing coat 160 will not actually be formed in metal
The surface of nanostructured 142.
In the present embodiment, finishing coat 160 can effectively suppress testing molecule (such as antigen or egg
White matter) it is sticky on the surface of substrate 100, except that can reduce because the non-specific combination of testing molecule is made
Into noise jamming, can also increase the probability that testing molecule is fixed on effective sensing area, and then lift sensing
Sensitivity and accuracy.
Fig. 2A to Fig. 2 C is according to the making stream of the sensor chip depicted in the second embodiment of the present invention
Journey generalized section.Herein it should be noted that, following embodiments continue to use previous embodiment part make
Flow, and follow-up manufacture craft is carried out after Fig. 1 D.Therefore, following embodiments will be continued to use foregoing
The element numbers and partial content of embodiment, wherein adopting the identical or approximate unit that is denoted by the same reference numerals
Part, and eliminate the explanation of constructed content.Explanation on clipped refers to foregoing implementation
Example, it is no longer repeated for following embodiments.
Fig. 2A is refer to, after metal Nano structure 142 as shown in figure iD is formed, is received with metal
Rice structure 142 is etching mask, carries out wet etching manufacture craft to substrate 100 and (e.g. uses
HF the or KOH aqueous solution), to form substrate 100a and multiple supporting constructions 202 disposed thereon,
Wherein supporting construction 202 is located between substrate 100a and metal Nano structure 142, so that metal nano
At a distance of a distance between structure 142 and substrate 100a.In the present embodiment, the depth of Wet-type etching is big
Cause is identical with the height H2 of supporting construction 202, can control supporting construction by controlling the time of etching
Height.The height H2 of supporting construction 202 is, for example, between 10nm to 100nm.
In the present embodiment, metal Nano structure 142 has upper surface 142a and lower surface 142b.
In the present embodiment, upper surface 142a is an arc-shaped surface, but the invention is not restricted to this.Lower surface 142b
With a corner regions 142c.There is contact surface 204 between lower surface 142b and supporting construction 202.By
In wet etching be isotropic etching, therefore during wet etching is carried out, except that can lose
Carve the exposed substrate 100 of outs open 144, also can lateral etch part metal Nano structure 142
The substrate 100 of lower section, thus contact surface 204 width L2 less than metal Nano structure 142 width
L1。
Then, Fig. 2 B are refer to, finishing coat 250 are formed on the surface of metal Nano structure 142,
It is used to catch the corresponding antibody of testing molecule or aptamer.Finishing coat 250 includes multiple with sulphur
The molecule 252 of alcohol radical (- SH).Molecule 252 with mercapto is, for example, 11- Mercaptoundecanoic acids
(11-mercaptoundecanoic acid, 11-MUA), 11- sulfydryl undecylamines
(11-Amino-1-undecanethiol, 11-AUT), cysteamine (Cysteamine), 4- aminothiophenols
(4-Aminothiophenol), 4- methylbenzene phenyl-sulfhydrates (4-Methylthiophenol), Thiolation nucleic acid are fitted
Body (thiolated aptamer) or its combination.The method for forming finishing coat 250 is, for example, by Fig. 2A
Shown overall structure is dipped in the solution of above-claimed cpd.During immersion, with mercapto
Molecule 252 one end mercapto and metal Nano structure 142 upper surface 142a, lower surface 142b
And the metal of corner regions 142c produces reaction to form covalent bond.
Although in fig. 2b it can be seen that finishing coat 250 is contacted with the supporting construction 202 of part,
But the merely illustrative use of Fig. 2 B, in the present embodiment, because the molecule 252 with mercapto only can be with gold
Category is reacted without being reacted with supporting construction 202 and substrate 100a, therefore only can be in metal nano knot
Finishing coat 250 is formed on upper surface 142a, the lower surface 142b and corner regions 142c of structure 142,
Finishing coat 250 can't be formed on the surface of supporting construction 202 and substrate 100a.
Additionally, in the present embodiment, antibody corresponding to testing molecule (such as antigen or protein) or
Aptamer effectively can be grafted with finishing coat 250, therefore can improve testing molecule and be fixed on chip
The probability of effective sensing area, and then lift the sensitivity of sensing.
In the present embodiment, because supporting construction 202 is located at substrate 100a and metal Nano structure 142
Between so that at a distance of a distance between metal Nano structure 142 and substrate 100a, can make to be located at metal
The corner regions 142c of nanostructured 142 is up transferred from substrate with the sensing focus of substrate 100a intersections
100a, favourable determinand is close to from all quarter, reduces the influence of fixed time space steric hindrance.Additionally,
The lateral erosion effect of Wet-type etching manufacture craft can empty the substrate below sensing focus, make sensing focus more naked
It is exposed in surrounding environment, and then improves the sensitivity of sensing.
Then, Fig. 2 C are refer to, on the surface of substrate 100a and on the surface of supporting construction 202
Finishing coat 260 is formed, is used to resist testing molecule adhesion.Finishing coat 260 includes multiple tools
There is the molecule 262 of silylation.Molecule 262 with silylation such as diethanol silane (Poly (ethylene
Glycol)-silane, PEG-silane), polyvinylpyrrolidone silane (Polyvinylpyrrolidone-silane,
PVP-silane), polyethylene glycol oxide silane (Polyethyleneoxide-silane, PEO-silane) or its group
Close.Formed finishing coat 260 method be, for example, the overall structure shown in Fig. 2 B is dipped to it is above-mentioned
In the solution of compound.During immersion, the silylation and substrate of the molecule 262 with silylation
The silica on the surface of 100a and supporting construction 202 produces reaction to form covalent bond.So far, i.e.,
Complete the making of sensor chip 20.
In the present embodiment, finishing coat 260 can effectively suppress testing molecule (such as antigen or egg
White matter) it is sticky on the surface of substrate 100a and supporting construction 202, except that can reduce because of to be measured point
Noise jamming caused by the non-specific combination of son, can also increase testing molecule and be fixed on effective sensing area
Probability, and then lift sensitivity and the accuracy of sensing.
Hereinafter, embodiments of the invention are enumerated so that more specifically the present invention will be described.However, not taking off
From spirit of the invention, suitably the material shown in following embodiment, application method etc. can be carried out
Change.Therefore, the scope of the present invention should not carry out limited interpretation with embodiment described below.
[the structure design experiment of LSPR sensor chips]
In this experiment, Fdtd Method (Finite-Difference-Time-Domain, FDTD) is used
Method carrys out analysis mode structure 1-3.Model configuration 1 has structure as shown in Figure 2 A, and wherein metal is received
The material of rice structure is gold；Model configuration 2 has structure as shown in figure iD, wherein metal nano knot
The material of structure is gold；The structure of model configuration 3 is similar to model configuration 2, and its difference is model configuration
3 nanostructured is the Dagwood metal Nano structure being made up of gold-aluminum oxide-gold.
Table 1 shows the sensitivity and manufacture craft yield by the model configuration 1-3 after the analysis of FDTD methods.
As shown in table 1, model configuration 1, model configuration 2 are respectively 331 with the sensitivity of model configuration 3
nm/RIU、230nm/RIU、280nm/RIU.From the above results, model configuration 1 has most
Sensitivity high and with manufacture craft yield high, therefore be adapted to be configured as model configuration 1
The structure of LSPR chips.
Table 1
| Sensitivity (nm/RIU) | Manufacture craft yield | |
| Model configuration 1 | 331 | It is high |
| Model configuration 2 | 230 | It is high |
| Model configuration 3 | 280 | It is low |
[sensitivity experiment of LSPR sensor chips]
Embodiment 1
Embodiment 1 is that (have carries out wet type to the sensor chip with structure as shown in Figure 2 A to substrate
Etching method manufacture craft).
The sensor chip of embodiment 1 is respectively placed in air (refractive index is 1.0) and water (refractive index
In 1.33), pushed away by measuring the change of its LSPR characteristic spectrum (characteristic spectra)
Calculate its sensitivity.Fig. 3 is characteristic spectrum of the sensor chip of embodiment 1 in air and water.Such as Fig. 3
It is shown, during the sensor chip of embodiment 1 moved into refractive index water higher by refractive index relatively low air,
Its characteristic spectrum red displacement 117nm because medium refraction index is raised, the sensitivity extrapolated according to this is 351
nm/RIU。
Comparative example 1
Comparative example 1 is that the sensor chip with structure as shown in figure iD (does not carry out wet type to substrate
Etching method manufacture craft).
The sensor chip of comparative example 1 is respectively placed in air (refractive index is 1.0) and water (refractive index
In 1.33), its sensitivity is calculated by measuring the change of its LSPR characteristic spectrum.Fig. 4 is ratio
Compared with the characteristic spectrum of the sensor chip in air and water of example 1.As shown in figure 4, by the sense of comparative example 1
Survey chip is moved in refractive index water higher by the relatively low air of refractive index, and its characteristic spectrum is because of medium refraction
Rate is raised and red displacement 63nm, and the sensitivity extrapolated according to this is 189nm/RIU.
From the above results, embodiment 1 has sensitivity higher compared to comparative example 1.
The FDTD analog results that Fig. 5 A are distributed for the energy hotspot of embodiment 1.Fig. 5 B are comparative example 1
Energy hotspot distribution FDTD analog results.Sensing focus 404 compared to comparative example 1 is located at base
The intersection of plate 400 and metal Nano structure 402, due to embodiment 1 metal Nano structure 302 with
It is spaced a distance between substrate 300 so that the sensing focus 304 of embodiment 1 is exposed, therefore embodiment
1 more favourable determinand is from all quarter close to sensing focus.
[influence of the etch depth to sensitivity]
By etching period can correspond to etched depth, therefore in order to further test with different etchings
The sensitivity of the sensor chip of depth, can carry out different time condition to sensor chip as shown in figure iD
Wet-type etching manufacture craft, and measure the spirit of sensor chip made by each different etching period condition
Sensitivity.Additionally, above-mentioned measured result is overlapped with corresponding FDTD analog results.Fig. 6
It is sensitivity experiment and the comparing figure of FDTD analog results.As shown in fig. 6, the result of sensitivity experiment
Trend with FDTD analog results is coincide.When the depth of etching is deeper, then manufactured sensor chip
Sensitivity is higher.This phenomenon can be explained by the position of the sensing focus of sensor chip, when etch depth is
When zero (structure as shown in figure iD), sensing focus is located at the intersection of metal Nano structure and substrate,
Therefore most energy is embedded in substrate, therefore the sensitivity of sensor chip is relatively low.However, with
The time of etching is (i.e. etch depth increases with lateral etch) more long, and sensing focus increases with the distance of substrate
Plus, in the sensing more exposed environment around of focus, therefore the sensitivity of sensor chip is higher.
[biotin-avidin system test]
In order to test the knot of the LSPR sensor chips actual test on biological specimen made by the present invention
Really, in the present embodiment, using with selectivity and affinity biotin-avidin higher
System (biotin-avidin system) is tested, wherein selected biotin is
NH2-PEG4-biotin, selected avidin is NeutrAvidin.NeutrAvidin goes for avidin
Modified form avidin after candy base, less likely produces sticky.
Embodiment 2 (carries out two benches surface modification)
First, sensor chip as shown in figure iD is steeped into the 11- amidos-undecane thiol in 0.1mM
24 hours in (11-amino-1-undecanethiol, 11-AUT) solution, to carry out first stage surface
Modification.Then, then by sensor chip 2- [methoxyl group (polyoxyethylene) propyl group] trimethoxy in 6mM is steeped
Silane (2- [Methoxy (polyethyleneoxy) propyl] trimethoxysilane, m-PEG silane) is molten
In liquid, 60 DEG C are heated in a nitrogen environment and is reacted 24 hours, to carry out second stage surface modification.
Then, by sensor chip bubble in 0.25% glutaraldehyde (glutaraldehyde, GTA) solution.Herein
During, the aldehyde radical of glutaraldehyde wherein one end can form covalent bond with the amido of 11-AUT.Afterwards, then
The NH2-PEG4-biotin solution of 1mM is dropped on sensor chip and rocked half an hour, in this process
In, the aldehyde radical of the glutaraldehyde other end can form covalent bond with the amido of NH2-PEG4-biotin.Then,
Sensor chip is cleaned with phosphate buffer solution.Afterwards, respectively by various concentrations (0.5 μ g/mL, 5 μ g/mL,
50 μ g/mL, 500 μ g/mL) NeutrAvidin solution drop on sensor chip and rock half an hour.
In the process, NH2-PEG4-biotin can and NeutrAvidin produce selectivity combination.
Comparative example 2 (only carries out the modification of single order section surface)
Using the similar method of such as embodiment 2, its difference is only that the sensor chip of comparative example 2 is only carried out
First stage (11-AUT) surface modification, does not carry out second stage (m-PEG silane) surface and repaiies
Decorations.
Fig. 7 is the graph of a relation of the testing molecule concentration red displacement of character pair spectrum of embodiment 2.Fig. 8 is
The graph of a relation of the testing molecule concentration red displacement of character pair spectrum of comparative example 2.
Fig. 7 is refer to, in 0.5~50 μ g/mL concentration ranges, with testing molecule (i.e. NeutrAvidin)
Concentration increase, the red displacement of characteristic spectrum also increases, that is to say, that testing molecule concentration and characteristic spectrum
Red displacement (can correspond to signal intensity) is a linear relationship, and this linear relationship is to testing molecule concentration
Can reach saturation and spectrum change is eased up because testing molecule completely spreads chip surface when being more than 50 μ g/mL.
Fig. 8 is refer to, the concentration with testing molecule increases, the red displacement of characteristic spectrum can't and then increase
Plus, that is to say, that testing molecule concentration is not linear relationship with the red displacement of characteristic spectrum.
Fig. 9 A are atomic force microscopy (Atomic Force Microscope, AFM) photo of embodiment 2.
Fig. 9 B are the atomic force micrograph of comparative example 2.Referring to Fig. 9 A and Fig. 9 B, by be measured
Chip after thing (i.e. NeutrAvidin) grafting, can be seen that by AFM image, be repaiied without two benches
The chip (i.e. comparative example 2) of decorations, has many determinands to adsorb in the group of being formed above at glass substrate
Poly-, surface roughness (Rq) is 6.7nm, it follows that substantial portion of determinand has lost
, also therefore influence the linear relationship of measurement of concetration.Comparatively, by two benches modify chip (i.e.
Embodiment 2), the adhesion of glass substrate is many less, and surface roughness (Rq) is 2.3nm, in theory not
Quantity loss is had, most determinand can be allowed only to be grafted with metal Nano structure, system can be improved
The stability and repeatability of measurement.
From the above results, because sensor chip of the invention has carried out two benches surface modification, therefore
Testing molecule adhesion can be avoided in non-sensing area, therefore the machine that testing molecule is grafted on sensing area can be improved
Rate, and then lift linear relationship of the testing molecule concentration to signal intensity.
In sum, make at a distance of a distance between the metal Nano structure and substrate of sensor chip of the invention
Focus must be sensed away from substrate and exposed, therefore with sensitivity higher.Additionally, sensing of the invention
Chip is grafted on effective sensing area by two stage surface modification except that can increase determinand
Probability, also reduces because determinand adhesion is in the noise jamming caused by non-sensing area, and then be lifted at not
With the sensitivity under testing molecule concentration with the linear relationship and raising sensing of signal.
Although disclosing the present invention with reference to above example, but it is not limited to the present invention, any
Those of ordinary skill in the art, without departing from the spirit and scope of the present invention, can do some
Perhaps change and retouching, therefore protection scope of the present invention should be with what the claim enclosed was defined
It is accurate.
Claims (15)
1. a kind of sensor chip, it is characterised in that the sensor chip includes：
Substrate；
Multiple metal Nano structures, on the substrate；
First surface decorative layer, on the surface of the metal Nano structure, wherein the first surface
Decorative layer includes multiple molecules with mercapto；And
Second surface decorative layer, on the surface of the substrate, the second surface decorative layer includes many
The individual molecule with silylation.
2. sensor chip according to claim 1, it is characterised in that：
The first surface decorative layer is located on the surface of the metal Nano structure, and is not located at the base
On the surface of plate, and
The second surface decorative layer is located on the surface of the substrate, and is not located at the metal nano knot
On structure.
3. sensor chip according to claim 1, it is characterised in that also including multiple supporting constructions,
Between the substrate and each metal Nano structure, so that each metal Nano structure and the base
At a distance of a distance between plate.
4. sensor chip according to claim 3, it is characterised in that the height of the supporting construction
For 10nm to 100nm.
5. sensor chip according to claim 3, it is characterised in that：
Each metal Nano structure has a upper surface and a lower surface, and
There is a contact surface, wherein the width of the contact surface between the lower surface and the supporting construction
Less than the width of each metal Nano structure.
6. sensor chip according to claim 5, it is characterised in that：
The lower surface have a corner regions, and the first surface decorative layer the molecule with mercapto
It is fixed on the upper surface of metal Nano structure, the lower surface and the corner regions.
7. sensor chip according to claim 3, it is characterised in that the second surface decorative layer
On surface positioned at each supporting construction with the substrate.
8. sensor chip according to claim 3, it is characterised in that the material of the supporting construction
Material with the substrate is identical.
9. sensor chip according to claim 1, it is characterised in that the metal Nano structure
Size is between 10nm to 900nm.
10. sensor chip according to claim 1, it is characterised in that the metal Nano structure
Height is between 10nm to 100nm.
11. sensor chips according to claim 1, it is characterised in that the metal Nano structure with
Periodically and systematicness is arranged on the substrate, cycle of the metal Nano structure between 15nm extremely
1000nm。
12. sensor chips according to claim 1, it is characterised in that the metal Nano structure
Shape includes cylindrical type, dome-type, disc type, moth ocular form, triangle column type or its combination.
13. sensor chips according to claim 1, it is characterised in that the metal Nano structure
Material includes silver, gold, platinum, copper, aluminium or its combination.
14. sensor chips according to claim 1, it is characterised in that the dividing with mercapto
Attached bag includes 11- Mercaptoundecanoic acids, 11- sulfydryls undecylamine, cysteamine, 4- aminothiophenols, 4- methyl
Benzenethiol, Thiolation aptamer or its combination.
15. sensor chips according to claim 1, it is characterised in that the dividing with silylation
Attached bag includes poly- diethanol silane, polyvinylpyrrolidone silane, polyethylene glycol oxide silane or its combination.
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