CN207181294U - Total-reflection type oblique incident ray difference in reflection scanned imagery device - Google Patents
Total-reflection type oblique incident ray difference in reflection scanned imagery device Download PDFInfo
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- CN207181294U CN207181294U CN201720885947.4U CN201720885947U CN207181294U CN 207181294 U CN207181294 U CN 207181294U CN 201720885947 U CN201720885947 U CN 201720885947U CN 207181294 U CN207181294 U CN 207181294U
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Abstract
The utility model category biosensor technology field, specially a kind of total-reflection type oblique incident ray difference in reflection scanned imagery device.The utility model device includes：Periodic modulation incident light polarization state, automatically adjust incident light converged state, the input path for being totally reflected incident light, the reflected light path of detection reflection light polarization state, accommodate and move the sample treatment unit of biochip, carry out the device management unit of data sampling and processing and system control.The outstanding advantages of the utility model device are that high sensitivity, flux be high, label-free, Real-time dynamics detection, 10,000 ~ 100,000 bio-molecular interactions can not only be detected simultaneously, and can effective detection molecular weight be about 500 Da small molecule, provide advanced, sensitive detection technique for application fields such as life science, new drug development, clinical diagnosises.
Description
Technical field
A kind of the utility model category biosensor technology field, and in particular to total-reflection type oblique incident ray difference in reflection scanning
Imaging device.
Background technology
Bio-molecular interaction is the basis that biological phenomena occurs, and analyzes biological disperser, for disclosing
The molecular mechanism of life process, the basic law tool of research biological phenomena occurrence and development are of great significance.And biology point
Quantum count is huge, and systematically analyzing biological disperser needs high-throughout analysis tool.Biochip technology is because of it
Up to ten thousand kinds of biological dispersers can be studied simultaneously, studied in genomics, proteomics, metabolism group etc.
In played important function.
At present, the optical bio sensing technology of conventional detection biochip fills including oblique incident ray difference in reflection scanning imagery
Put, reflection interference spectrum imager, resonance waveguide optical grating sensor etc..Wherein, oblique incident ray difference in reflection scanned imagery device is adopted
Fast modulation is carried out to incident light polarization state with light polarization modulator, the harmonic signal of modulation is not handed over by mechanical oscillation and civil power
The influence of signal is flowed, system noise is small, and signal to noise ratio is high.Oblique incident ray difference in reflection scanned imagery device uses lens focus incident light
Biochip scanning is imaged, scan area do not limit, and can include 10,000 ~ 100,000 lifes to a width of 2 cm, a length of 5 cm
The biochip of thing sample is scanned.The detection flux of oblique incident ray difference in reflection scanned imagery device（Single experiment detection 10,000
~ 10 ten thousand bio-molecular interactions）Far above other optical bio sensing devices, and should in other optical bio sensing devices
It is applied widely with less high-throughput drug primary dcreening operation field.
Oblique incident ray difference in reflection technology is highly sensitive optical detecting method developed in recent years, has sensitivity
Height, not damaged, the outstanding feature such as measurement in real time in situ.The Full-automatic oblique incidence light reflection difference that the present inventor is developed with partner is swept
Imaging device is retouched, the fast imaging by the way of optical scanning and mechanical scanning are combined is real with reference to sample treatment and fluid system
Show the quick of biochip, high flux, full-automatic detection, be specifically shown in bibliography Y.Y. Fei et al, Review of
Scientific Instruments, 79,013708 (2008) and utility model patent（The patent No.：
2015202684443）.The outstanding advantages of oblique incident ray difference in reflection scanned imagery device are high fluxs, can detect 10 cm2Pass
10,000 in sensillary area domain ~ 100,000 bio-molecular interactions and the interaction of detection molecules of the molecular weight more than 1000Da.But
Be, oblique incident ray difference in reflection scanned imagery device can not detection molecules amount be less than fM protein molecular less than 1000Da or concentration,
Limit its application in the field such as pharmacokinetics and disease detection.At present, oblique incident ray difference in reflection scanning imagery field is ground
Study carefully personnel and temporarily improve oblique incident ray difference in reflection scanned imagery device sensitivity technique small molecule or low concentration albumen without proposition
Effective scheme.It is still one that develop has high flux and highly sensitive oblique incident ray difference in reflection scanned imagery device simultaneously
Challenge.
The content of the invention
The purpose of this utility model is the total reflection for providing a kind of high flux, highly sensitive, label-free detection biochip
Formula oblique incident ray difference in reflection scanned imagery device.
Total-reflection type oblique incident ray difference in reflection scanned imagery device provided by the utility model, be based on zoom lens,
Including：Periodic modulation incident light polarization state, automatically adjust incident light converged state, the incidence for being totally reflected incident light
Light path, the reflected light path of detection reflection light polarization state, is accommodated and the sample treatment unit of mobile biochip, progress data are adopted
The device management unit of collection, processing and system control.The input path, sample treatment unit, reflected light path and equipment control
Unit is arranged in order.
The periodic modulation incident light polarization state, automatically adjust incident light converged state, incident light is all-trans
The input path penetrated, including monochromatic optical generator, light polarization modulator, zoom lens and prism, and be arranged in order in the order.Its
In：
Described monochromatic optical generator includes continuous spectrum light source and light-splitting device, or is single color light emitting devices.
The light-splitting device is spectrometer or optical filter.
The single color light emitting devices are laser or light emitting diode.
Described light polarization modulator is light ball modulator, electro-optic phase modulator, rotating wave plate, rotatable polarizer or rotation
Reflector.
Described zoom lens are single zoom lens or combination zoom lens.
Described single zoom lens are the flexible zoom lens that power mutagens shape drives or electrostrictive drives.
Described single zoom lens are the zoom lens for the response time being less than 20 ms.
Described combination zoom lens include universal focus lens and single zoom lens.
Described universal focus lens is telecentric lens, field flattening lens, cylindrical lens or spherical lens.
Described telecentric lens or field flattening lens is applied in combination with scanning galvanometer.
Described universal focus lens and single zoom lens spacing are the cm of 1 cm ~ 50.
Described prism is equilateral prism, Dove prism, polygon prism or semicolumn prism.
Described prism is optical glass, the prism of quartz glass preparation.
Described prism side size range is the mm of 1 mm ~ 60, and thickness range is the mm of 1 mm ~ 60.
The periodic modulation incident light polarization state, automatically adjust incident light converged state, incident light is all-trans
The input path penetrated, in addition to determine for producing the polarizer of polarization state, the polarizer be located at monochromatic optical generator and inclined
Shake between modulator.
The described polarizer is devating prism, reflective polarizer, scatter-type polarizer or dichroism linear polarization.
The periodic modulation incident light polarization state, automatically adjust incident light converged state, incident light is all-trans
The input path penetrated, in addition to for introducing the phase-shifter of adjustable phase change, the phase-shifter is between the polarizer and prism
Optional position.
Described phase-shifter is bubble Ke Ersi boxes, kerr cell, liquid crystal phase retardation device, wave plate, Babinet's compensator, Soret
Compensator or Berek compensator.
The periodic modulation incident light polarization state and automatically adjust incident light converged state input path incidence
Angular region is 30 ° ~ 85 °.
Described receiving and the sample treatment unit of mobile biochip, including biochip, biochip support peace
Moving stage, biochip are fixed on biochip support, and biochip support is connected on translation stage.Wherein：
Described translation stage is driving stepper motor, the motor machine translation stage of DC servo motor driving.
The transparent substrate of described biochip is slide, the slide of plating metal on surface film or surface gold-plating metal particles
Slide.
Described slide is slide made of optical glass or quartz glass.
Described metal film is golden film, silverskin, chromium film or metallized multilayer film.
Described thickness of metal film scope is the nm of 10 nm ~ 80.
Described metallic particles is gold grain, Argent grain or metal mixed particle.
The particle size range of described metallic particles is the nm of 1 nm ~ 80.
Described metal film or metallic particles are located at slide lower surface or in prism lower surfaces.
The reflected light path of the detection reflection light polarization state includes analyzer and photodetector；Wherein：
Described analyzer is devating prism, reflective polarizer, scatter-type polarizer or dichroism linear polarization.
Described photodetector is linear photodiode, photodiode array, charge coupling device image sensing
Device or cmos image sensor.
The device management unit for carrying out data sampling and processing and system control, including data acquisition unit and system
Control unit.Wherein：
Described data acquisition unit includes data collecting card and data processor.
The data processor is the number of lock-in amplifier, frequency spectrum analyser, oscillograph or application Fourier analysis algorithm
According to processor.
Total-reflection type oblique incident ray difference in reflection scanned imagery device of the present utility model, in addition to cushioning liquid pump, sample
The liquid-treatment unit of solution pump, selector valve and switching valve composition.Sample fluid pump is connected with first choice valve, first choice valve
It is connected with switching valve, switching valve is connected with the second selector valve, and the second selector valve is connected with fluid cavity, cushioning liquid pump and switching valve
Connection.
The utility model is totally reflected oblique incident ray difference in reflection scanned imagery device under mode of operation using zoom lens development,
With following outstanding advantages：
（1）High sensitivity：Can detection molecules amount be about 500 Da small molecule and concentration close to fM protein molecular,
Application of the device in bio-sensing field has been widened significantly；
（2）Flexibility is strong：Without complicated fluid system, a drop water reaction can be provided needed for liquid environment, carry significantly
High operating flexibility, basis is provided to develop simple, quick medical science detection and diagnostic instrments；
（3）It is compatible strong：The biochip of metal-coated membrane and non-metal-coated membrane can be detected by the device high flux, different
The compatible detection of the chip outstanding advantage such as make the equipment have wide dynamic range, measurement range wide.
Brief description of the drawings
Fig. 1 is total-reflection type oblique incident ray difference in reflection scanned imagery device the first schematic diagram based on zoom lens.
Fig. 2 is that incident light reflects at the hypotenuse of prism, and incident beam is after glass substrate when prism moves right
Surface not refocusing.
Fig. 3 is total-reflection type oblique incident ray difference in reflection second of schematic diagram of scanned imagery device based on zoom lens.
Fig. 4 is total-reflection type oblique incident ray difference in reflection scanned imagery device the third schematic diagram based on zoom lens.
Label in figure：1 monochromatic optical generator, 2,4 be speculum, and 3 be beam expander, and 5 be the polarizer, and 6 be Polarization Modulation
Device；7 be phase-shifter；8 be single zoom lens；9 be universal focus lens；10 be prism, and 11 be lens, and 12 be analyzer；13
It is photodiode for slit, 14,15 be amplifying circuit, and 16 be data acquisition unit, and 17 be system control unit, and 18 be transparent
Substrate, 19 metal films, 20 be biological sample, and 21 be biological chip set, and 22 be translation stage, and 23 be drop.
Embodiment
Below in conjunction with the accompanying drawings and embodiment further describes the utility model：
X the and y directions composition horizontal plane marked in accompanying drawing, wherein x directions are the horizontal direction of horizontal plane, and y directions are water
The longitudinal direction of plane.Z directions are perpendicular to the direction of horizontal plane.
Embodiment 1：
Refer to the attached drawing 1, the utility model provide a kind of total-reflection type oblique incident ray difference in reflection scanning based on zoom lens
Imaging device, the device include input path, reflected light path, sample treatment unit and device management unit.
Input path is used for periodic modulation incident light polarization state, automatically adjusts incident light converged state, sends out incident light
Raw total reflection and by incident light oblique incidence to sample surfaces.Input path specifically includes：
Monochromatic optical generator 1 can be continuous spectrum light source and light-splitting device or single color light emitting devices, and light-splitting device can be with
It is spectrometer or optical filter, single color light emitting devices can be laser or light emitting diode.Monochromatic optical generator 1 is used to provide list
The incident light of wavelength.Speculum 2 and 4 can be the high reflectivity mirror for plating silverskin, for changing and finely tuning the biography of incident light
Broadcast direction.Beam expander 3 can be fixed multiplying power or the beam expander of adjustable multiplying power, parallel for incident light to be expanded into collimation
Light, reduce incident light and pass through the error that follow-up polarization optical element is brought.The polarizer 5 can be devating prism, reflection type polarization
Device, scatter-type polarizer or dichroism linear polarization, for by incident light be changed as direction of vibration and p-polarization direction into
45 ° of linearly polarized light.Light polarization modulator 6 can be light ball modulator, electro-optic phase modulator, rotating wave plate, rotatable polarizer
Or rotoflector device, for the polarization state of high speed periodic modulation incident light, improve detection speed and signal to noise ratio.Phase-shifter
7 can be bubble Ke Ersi boxes, kerr cell, liquid crystal phase retardation device, wave plate, Babinet's compensator, Soret compensator or shellfish rake
Compensator, for introducing fixed phase difference between p-polarization and s polarizations, so as to the Substrate signal that returns to zero, reduce noise.
Zoom lens can be single zoom lens 8 or combination zoom lens 8 and 9.Single zoom lens 8 can be that power causes
Deformation driving or the flexible zoom lens of electrostrictive driving, can be in response to zoom lens of the time less than 20 ms, Ke Yishi
The zoom lens that adjustable range is the dpt of -3 dpt ~ 5, zoom accuracy is ± 0.01 dpt.It can be fixed to combine zoom lens
Focal length lenses 9 combine with single zoom lens 8, universal focus lens 9 can be telecentric lens, field flattening lens, cylindrical lens or
Spherical lens, telecentric lens or field flattening lens can be applied in combination with scanning galvanometer, universal focus lens 9 and single zoom lens
8 spacing can be the cm of 1 cm ~ 50.Zoom lens are used in biochip and the common moving process in the x-direction of prism in real time
The convergence property of incident beam is adjusted, solving biochip drive prism, incident light can not be all the time during the movement of x directions
The problem of focusing on biochip lower surface.In addition, combination zoom lens are additionally operable to make light be scanned or be focused in the z-direction
It is linear, z direction signal detections are carried out to biochip.Biochip movement is driven to realize x with reference to stepping mechanically moving translation stage
Direction signal is detected, and oblique incident ray difference in reflection scanned imagery device is imaged to biochip.Using the incidence of prism-coupled
Light can not focus on the reason for biochip lower surface all the time as shown in Figure 2.Original hypothesis incident light focuses on biochip
The right side edge of 18 lower surfaces.When biochip 18 and prism 10 move right jointly, incident light is at the hypotenuse of prism 10
Reflect, refraction light relative to incident light closer to hypotenuse normal direction so as to become to dissipate, the convergence property of incident light
Change, lead to not the lower surface for focusing on biochip.Adjust the convergence of incident beam on demand using zoom lens
Matter, successfully solve the problems, such as to focus on.
Prism 10 can be equilateral prism, Dove prism, polygon prism or semicolumn prism, can be optical glass, stone
The prism of English glass preparation can be side size range for the mm of 1 mm ~ 60, and thickness range is the mm of 1 mm ~ 60 prism.Rib
Mirror 10 is placed on the top of biochip 18 and exerted a force after the uniformly one layer of index-matching fluid of addition that be situated between by the He of prism 10
Biochip 18 is fixed together.Incident light can to 18 surfaces, ranges of incidence angles under biochip by the oblique incidence of prism 10
To be 30 ° ~ 85 °.Prism 10 is used to make incident light produce total reflection in the lower surface of biochip 18 and liquid solution interface, suddenly
The ripple that dies penetrates the metal level of biochip 18 and interacted with the free electron of metal level, inspires the table propagated along metal surface
Face plasma wave.In addition, prism can also increase the wave vector of incident light in the x-direction, the wave vector of match surface phasmon is so as to sharp
Send out surface phasmon.
Reflected light path is used to detect reflection light polarization state and optical signalling is converted into electronic signal.Reflected light path is specific
Including：
Lens 11 can be post lens, for reflected light to be focused into a line.Analyzer 12 can be devating prism, anti-
Emitting polarizer, scatter-type polarizer or dichroism linear polarization, for p-polarization and s polarizations to be projected into identical side
To so as to detecting the polarization state of reflected light.Slit 13 is used for the reflected light by producing surface plasmon resonance and prevented not
Produce the reflected light of surface plasmon resonance.Photodetector 14 can be linear photodiode, photodiode array,
Charge coupling device imaging sensor or cmos image sensor.Photodetector 14 is used to believe light
Number electric signal is converted into, and exports electronic signal and be used for follow-up measurement.
Sample treatment unit is used to accommodate and mobile biochip, specifically includes：
Biochip support 21 can be fluid cavity, for providing the liquid environment of flowing for biochip, and by biology
It can be driving stepper motor, the motor machine translation of DC servo motor driving that chip, which is placed on xz plane translations platform 22,
Platform, can have the translation stage of encoder or the translation stage without encoder.Translation stage is used for stepping in the x-direction and moves biological core
Piece detects the signal in x directions.Biochip transparent substrate 18 can be the slide or surface gold-plating of plating metal on surface film 19
The slide of metal particles 19.Slide can be slide made of optical glass or quartz glass.Metal film can be golden film,
Silverskin, chromium film or metallized multilayer film can be thickness ranges for the nm of 10 nm ~ 80 metal film.Metallic particles can be gold
Particle, Argent grain or metal mixed particle, can be the nm of the nm of size 1 ~ 80 metallic particles.Metal film 19 and metallic particles
19 can be in the lower surface of slide 18 or in the lower surface of prism 10.Biochip is used to fill for oblique incident ray difference in reflection scanning imagery
Put and biological sample and its carrier to be measured are provided, wherein metal film is used to provide the free electron for producing surface phasmon.Focus on
The incident angular breadth of incident light is 3 ° ~ 5 °, and under the conditions of specific incidence angle, the wave vector of incident light in the prism is in the x-direction
Projection is equal with surface phasmon inherence propagation wave vector, and total reflection evanescent wave resonates with surface phasmon, incident light
Most of energy absorbed by surface phasmon so that energy of reflection light drastically declines, so as to resonance absorbing peak occur, this angle
Degree is referred to as resonance angle.Under resonance angle, oblique incident ray reflection difference signal is enhanced 10 ~ 100 times, and detection sensitivity will be carried significantly
It is high.
Device management unit is used for data sampling and processing and system controls, and specifically includes：
Direct current signal in the electric signal that amplifying circuit 15 is used to input photodetector 14 is filtered, and AC signal is put
Greatly.Data acquisition unit 16 can be data collecting card and data processor, and data processor can be lock-in amplifier, frequency spectrum
The data processor of analyzer, oscillograph or application Fourier analysis algorithm.System control unit can be microcomputer, use
Motion control, fluid control and data processing in whole device.
Total-reflection type oblique incident ray difference in reflection scanned imagery device based on zoom lens, in addition to cushioning liquid pump, sample
The liquid-treatment unit of product solution pump, selector valve and switching valve composition.Specific connected mode and purposes are：Sample fluid pump and
One selector valve is connected, and first choice valve is connected with switching valve, for cleaning syringe, pipette samples, sample being stored in into injection
With in certain speed injection fluid cavity in device and by the sample of certain volume；Cushioning liquid pump connects with switching valve, switching valve
It is connected with the second selector valve, for drawing cushioning liquid, by buffer storage in syringe and the buffering of certain volume is molten
Liquid injects fluid cavity with certain speed.Referring specifically to patent（Application number：2015102112203）.
Embodiment 2：
The utility model of refer to the attached drawing 3 provides another total-reflection type oblique incident ray difference in reflection scanning based on zoom lens
Imaging device, the device include：The device includes input path, reflected light path, sample treatment unit and device management unit.
Unlike in the structure of accompanying drawing 1：Directly point prints biological sample 20 to be measured to biochip on slide 18, without
Metal film 19.Lens 11 can be that object lens or convex lens replace post lens.Slit 13 allow whole reflected lights by and incide
On photodetector 14.
Input path is used for periodic modulation incident light polarization state, automatically adjusts incident light converged state, sends out incident light
Raw total reflection and by incident light oblique incidence to sample surfaces.Input path specifically includes：
Monochromatic optical generator 1 can be continuous spectrum light source and light-splitting device or single color light emitting devices, and light-splitting device can be with
It is spectrometer or optical filter, single color light emitting devices can be laser or light emitting diode.Monochromatic optical generator 1 is used to provide list
The incident light of wavelength.Speculum 2 and 4 can be the high reflectivity mirror for plating silverskin, for changing and finely tuning the biography of incident light
Broadcast direction.Beam expander 3 can be fixed multiplying power or the beam expander of adjustable multiplying power, parallel for incident light to be expanded into collimation
Light, reduce incident light and pass through the error that follow-up polarization optical element is brought.The polarizer 5 can be devating prism, reflection type polarization
Device, scatter-type polarizer or dichroism linear polarization, for by incident light be changed as direction of vibration and p-polarization direction into
45 ° of linearly polarized light.Light polarization modulator 6 can be light ball modulator, electro-optic phase modulator, rotating wave plate, rotatable polarizer
Or rotoflector, for the polarization state of high speed periodic modulation incident light, improve detection speed and signal to noise ratio.Phase-shifter 7
Can be that bubble Ke Ersi boxes, kerr cell, liquid crystal phase retardation device, wave plate, Babinet's compensator, Soret compensator or shellfish rake are mended
Device is repaid, for introducing fixed phase difference between p-polarization and s polarizations, so as to the Substrate signal that returns to zero, reduces noise.
Zoom lens can be single zoom lens 8 or combination zoom lens 8 and 9.Single zoom lens 8 can be that power causes
Deformation driving or the flexible zoom lens of electrostrictive driving, can be in response to zoom lens of the time less than 20 ms, Ke Yishi
The zoom lens that adjustable range is the dpt of -3 dpt ~ 5, zoom accuracy is ± 0.01 dpt.Combination zoom lens can be solid
Determine focal length lenses 9 to combine with single zoom lens 8, universal focus lens 9 can be telecentric lens, field flattening lens, cylindrical lens
Or spherical lens, telecentric lens or field flattening lens can be applied in combination with scanning galvanometer, universal focus lens 9 and single zoom are saturating
The spacing of mirror 8 can be the cm of 1 cm ~ 50.Zoom lens are used for real in biochip and the common moving process in the x-direction of prism
When adjust incident beam convergence property, solve biochip with prism x directions move during incident light can not be all the time
The problem of focusing on biochip lower surface.In addition, combination zoom lens are additionally operable to make light be scanned or be focused in the z-direction
It is linear, z direction signal detections are carried out to biochip.
Prism 10 can be equilateral prism, Dove prism, polygon prism or semicolumn prism, can be optical glass, stone
The prism of English glass preparation can be side size range for the mm of 1 mm ~ 60, and thickness range is the mm of 1 mm ~ 60 prism.Rib
Mirror 10 is placed on the top of biochip 18 and exerted a force after the uniformly one layer of index-matching fluid of addition that be situated between by the He of prism 10
Biochip 18 is fixed together.Incident light can to 18 surfaces, ranges of incidence angles under biochip by the oblique incidence of prism 10
To be 30 ° ~ 85 °.Prism 10 is used to make incident light produce total reflection in the lower surface of biochip 18 and liquid solution interface, suddenly
The penetration depth of ripple in a liquid that dies is only wavelength magnitude, greatly reduces background noise, improves oblique incidence to a certain extent
The detection sensitivity of light reflection difference scanned imagery device.
Reflected light path is used to detect reflection light polarization state and optical signalling is converted into electric signal.Reflected light path specifically wraps
Include：
Lens 11 can be narrow for the launching spot for being incident on the lower surface of biochip transparent substrate 18 to be imaged in object lens
The position of seam 13.Analyzer 12 can be devating prism, reflective polarizer, scatter-type polarizer or dichroism linear polarization
Device, for p-polarization and s polarizations to be projected into identical direction so as to detect the polarization state of reflected light.Slit 13 is used for will be raw
The reflected light of the lower surface of thing chip transparent substrate 18 is all incided on photodetector 14.Photodetector 14 can be linear
Photodiode, photodiode array, charge coupling device imaging sensor or complementary metal-oxide-semiconductor image pass
Sensor.Photodetector 14 is used to convert optical signal into electric signal, and exports electric signal and be used to subsequently measure.
Sample treatment unit is used to accommodate and mobile biochip, specifically includes：
Biochip support 21 can be fluid cavity, for providing the liquid environment of flowing for biochip.Translation stage 22
Can be driving stepper motor, DC servo motor driving motor machine translation stage, can be have encoder translation stage or
There is no the translation stage of encoder.Translation stage is used for the movement biochip of stepping in the x-direction to detect the signal in x directions.Biological core
Piece transparent substrate 18 can be slide, and slide can be slide made of optical glass or quartz glass.Biochip
For providing biological sample and its carrier to be measured for oblique incident ray difference in reflection scanned imagery device.It is totally reflected evanescent wave in the solution
Penetration depth be wavelength magnitude, be capable of it is sensitive sensing biochip surface thickness change and carry out the highly sensitive optics of high flux
Bio-sensing.Total-reflection type oblique incident ray difference in reflection scanned imagery device based on zoom lens can either be detected delicately very much
The biochip prepared on the slide of metal-coated membrane, the biology prepared on common slide also can be delicately detected enough
Chip, system compatibility are strong.With reference to two kinds of mode of operations, the dynamic range of the device can be widened, so as to widen application.
Device management unit is used for data sampling and processing and system controls, and specifically includes：
Direct current signal in the electric signal that amplifying circuit 15 is used to input photodetector 14 is filtered, and AC signal is put
Greatly.Data acquisition unit 16 can be data collecting card and data processor, and data processor can be lock-in amplifier, frequency spectrum
The data processor of analyzer, oscillograph or application Fourier analysis algorithm.System control unit can be microcomputer, use
Motion control, fluid control and data processing in whole device.
Total-reflection type oblique incident ray difference in reflection scanned imagery device based on zoom lens, in addition to cushioning liquid pump, sample
The liquid-treatment unit of product solution pump, selector valve and switching valve composition.Specific connected mode and purposes are：Sample fluid pump and
One selector valve is connected, and first choice valve is connected with switching valve, for cleaning syringe, pipette samples, sample being stored in into injection
With in certain speed injection fluid cavity in device and by the sample of certain volume；Cushioning liquid pump connects with switching valve, switching valve
It is connected with the second selector valve, for drawing cushioning liquid, by buffer storage in syringe and the buffering of certain volume is molten
Liquid injects fluid cavity with certain speed.Referring specifically to patent（Application number：2015102112203）.
Embodiment 3：
The utility model of refer to the attached drawing 4 provides another total-reflection type oblique incident ray difference in reflection scanning based on zoom lens
Imaging device, the device include：The device includes input path, reflected light path, sample treatment unit and device management unit.
Unlike in the structure of accompanying drawing 1：Biochip is no longer placed in fluid cavity, uses drop 23 as biochip
Liquid environment is provided；Biochip is placed in x/y plane, is no longer placed in xz planes；Optical scanning scans in the y-direction, translation
Platform scans in the x-direction.
Input path is used for periodic modulation incident light polarization state, automatically adjusts incident light converged state, sends out incident light
Raw total reflection and by incident light oblique incidence to sample surfaces.Input path specifically includes：
Monochromatic optical generator 1 can be continuous spectrum light source and light-splitting device or single color light emitting devices, and light-splitting device can be with
It is spectrometer or optical filter, single color light emitting devices can be laser or light emitting diode.Monochromatic optical generator 1 is used to provide list
The incident light of wavelength.Speculum 2 and 4 can be the high reflectivity mirror for plating silverskin, for changing and finely tuning the biography of incident light
Broadcast direction.Beam expander 3 can be fixed multiplying power or the beam expander of adjustable multiplying power, parallel for incident light to be expanded into collimation
Light, reduce incident light and pass through the error that follow-up polarization optical element is brought.The polarizer 5 can be devating prism, reflection type polarization
Device, scatter-type polarizer or dichroism linear polarization, for by incident light be changed as direction of vibration and p-polarization direction into
45 ° of linearly polarized light.Light polarization modulator 6 can be light ball modulator, electro-optic phase modulator, rotating wave plate, rotatable polarizer
Or rotoflector, for the polarization state of high speed periodic modulation incident light, improve detection speed and signal to noise ratio.Phase-shifter 7
Can be that bubble Ke Ersi boxes, kerr cell, liquid crystal phase retardation device, wave plate, Babinet's compensator, Soret compensator or shellfish rake are mended
Device is repaid, for introducing fixed phase difference between p-polarization and s polarizations, so as to the Substrate signal that returns to zero, reduces noise.
Zoom lens can be single zoom lens 8 or combination zoom lens 8 and 9.Single zoom lens 8 can be that power causes
Deformation driving or the flexible zoom lens of electrostrictive driving, can be in response to zoom lens of the time less than 20 ms, Ke Yishi
The zoom lens that adjustable range is the dpt of -3 dpt ~ 5, zoom accuracy is ± 0.01 dpt.Combination zoom lens can be solid
Determine focal length lenses 9 to combine with single zoom lens 8, universal focus lens 9 can be telecentric lens, field flattening lens, cylindrical lens
Or spherical lens, telecentric lens or field flattening lens can be applied in combination with scanning galvanometer, universal focus lens 9 and single zoom are saturating
The spacing of mirror 8 can be the cm of 1 cm ~ 50.Zoom lens are used in biochip and the common moving process in the x-direction of prism in real time
The convergence property of incident beam is adjusted, solving biochip drive prism, incident light can not be all the time during the movement of x directions
The problem of focusing on biochip lower surface.In addition, combination zoom lens are additionally operable to make light be scanned or be focused in the y-direction
It is linear, biochip is detected.
Prism 10 can be equilateral prism, Dove prism, polygon prism or semicolumn prism, can be optical glass, stone
The prism of English glass preparation can be side size range for the mm of 1 mm ~ 60, and thickness range is the mm of 1 mm ~ 60 prism.Rib
Mirror 10 is placed on the top of biochip 18 and exerted a force after the uniformly one layer of index-matching fluid of addition that be situated between by the He of prism 10
Biochip 18 is fixed together.Incident light can to 18 surfaces, ranges of incidence angles under biochip by the oblique incidence of prism 10
To be 30 ° ~ 85 °.Prism 10 is used to make incident light produce total reflection in the lower surface of biochip 18 and liquid solution interface, suddenly
The penetration depth of ripple in a liquid that dies is only wavelength magnitude, greatly reduces background noise, improves oblique incidence to a certain extent
The detection sensitivity of light reflection difference scanned imagery device.
Reflected light path is used to detect reflection light polarization state and optical signalling is converted into electronic signal.Reflected light path is specific
Including：
Lens 11 can be post lens, for reflected light to be focused into a line.Analyzer 12 can be devating prism, anti-
Emitting polarizer, scatter-type polarizer or dichroism linear polarization, for p-polarization and s polarizations to be projected into identical side
To so as to detecting the polarization state of reflected light.Slit 13 is used for the reflected light by producing surface plasmon resonance and prevented not
Produce the reflected light of surface plasmon resonance.Photodetector 14 can be linear photodiode, photodiode array,
Charge coupling device imaging sensor or cmos image sensor.Photodetector 14 is used to believe light
Number electric signal is converted into, and exports electronic signal and be used for follow-up measurement.
Sample treatment unit is used to accommodate and mobile biochip, specifically includes：
Biochip support 21 can be that biochip is fixed on mechanical translation platform 22 by support.Translation stage 22 can be
Driving stepper motor, the motor machine translation stage of DC servo motor driving, can have the translation stage of encoder or do not compile
The translation stage of code device.Translation stage is used for the movement biochip of stepping in the x-direction to detect the signal in x directions.Biochip is transparent
Substrate 18 can be the slide of plating metal on surface film 19 or the slide of surface gold-plating metal particles 19.Slide can be optics
Slide made of glass or quartz glass.Metal film can be golden film, silverskin, chromium film or metallized multilayer film, can be thickness
Scope is the nm of 10 nm ~ 80 metal film.Metallic particles can be gold grain, Argent grain or metal mixed particle, Ke Yishi
The nm of the nm of size 1 ~ 80 metallic particles.Metal film 19 and metallic particles 19 can be in the lower surfaces of slide 18 or in prism 10
Lower surface.Biochip is used to provide biological sample and its carrier to be measured for oblique incident ray difference in reflection scanned imagery device, wherein
Metal film is used to provide the free electron for producing surface phasmon.The incident angular breadth for focusing on incident light is 3 ° ~ 5 °, specific
Incidence angle under the conditions of, the projection of the wave vector of incident light in the prism in the x-direction and surface phasmon inherence propagation wave vector phase
Deng, total reflection evanescent wave resonated with surface phasmon, most of energy of incident light is absorbed by surface phasmon, makes
Obtain energy of reflection light drastically to decline, so as to resonance absorbing peak occur, this angle is referred to as resonance angle.Under resonance angle, oblique incident ray is anti-
It is enhanced 10 ~ 100 times to penetrate difference signal, detection sensitivity will be likely to rise dramatically.Place drop and be used to carry in biochip upper surface
Environment for liquid, without the fluid system of complexity, a drop water reaction can be provided needed for liquid environment, it is flexible to greatly improve operation
Property, provide basis to develop simple, quick medical science detection and diagnostic instrments；
Device management unit is used for data sampling and processing and system controls, and specifically includes：
Direct current signal in the electric signal that amplifying circuit 15 is used to input photodetector 14 is filtered, and AC signal is put
Greatly.Data acquisition unit 16 can be data collecting card and data processor, and data processor can be lock-in amplifier, frequency spectrum
The data processor of analyzer, oscillograph or application Fourier analysis algorithm.System control unit can be microcomputer, use
In the motion control and data processing of whole device.
Embodiment 4：
The utility model embodiment 4 provides a kind of total-reflection type oblique incident ray difference in reflection based on zoom lens and is scanned into
As the application method of device.（1）Biochip is installed on fluid cavity, smears one layer of index-matching fluid in biochip table
Face, prism is installed to biochip surface and is fixed on biochip support.（2）Cushioning liquid is filled with fluid cavity, it is right
Biochip scanning is imaged, and translation stage changes zoom lens focal length after often moving several step-lengths.（3）Made on biochip image
The coordinate data grid file of standby collection real time data, coordinate data had both included the centre coordinate of biological sample point, and had also included life
The coordinate of bare substrate point near thing sample.（4）Biochip is passed through into cushioning liquid flowing, while records institute in grid file
The signal for having number of coordinates strong point changes with time；Sample solution is then filled with fluid cavity and flows through biochip, continues to remember
The signal at all number of coordinates strong points changes with time in record grid file；Cushioning liquid is finally flowed through into fluid cavity, continues to remember
The signal at all number of coordinates strong points changes with time in record grid file, completes the real-time measurement of bio-molecular interaction.
With taking image similar, translation stage changes zoom lens focal length after often moving several step-lengths.（5）Reacted biochip is swept
Imaging is retouched, translation stage changes zoom lens focal length after often moving several step-lengths.
Claims (17)
- A kind of 1. total-reflection type oblique incident ray difference in reflection scanned imagery device, it is characterised in that including：Periodic modulation incident light Polarization state, automatically adjust incident light converged state, the input path for being totally reflected incident light, detection reflection light polarization shape The sample treatment unit of the reflected light path of state, receiving and mobile biochip, progress data sampling and processing and system control are set Standby administrative unit；The input path, sample treatment unit, reflected light path and device management unit are arranged in order.
- 2. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 1, it is characterised in that：Described input path, including monochromatic optical generator, light polarization modulator, zoom lens and prism, and in the order successively Arrangement；Described sample treatment unit, including biochip, biochip support and translation stage, biochip are fixed on biological core On plate rack, biochip support is connected on translation stage；Described device management unit, including data acquisition unit and system control unit.
- 3. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 2, it is characterised in that：Described monochromatic optical generator includes continuous spectrum light source and light-splitting device, or is single color light emitting devices；The optical splitter Part is spectrometer or optical filter；The single color light emitting devices are laser or light emitting diode；Described light polarization modulator is light ball modulator, electro-optic phase modulator, rotating wave plate, rotatable polarizer or rotary reflection Device；Described zoom lens are single zoom lens or combination zoom lens；Described prism is equilateral prism, Dove prism, polygon prism or semicolumn prism.
- 4. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 3, it is characterised in that described The flexible zoom lens that single zoom lens are the driving of power mutagens shape or electrostrictive drives, the sound of described single zoom lens It is less than 20 ms between seasonable.
- 5. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 3, it is characterised in that described Combination zoom lens include universal focus lens and single zoom lens；Described universal focus lens is telecentric lens, flat field Lens, cylindrical lens or spherical lens；Described prism is equilateral prism, Dove prism, polygon prism or semicolumn prism；Institute The material for the prism stated is optical glass or quartz glass.
- 6. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 5, it is characterised in that described Universal focus lens and single zoom lens spacing are the cm of 1 cm ~ 50；The described prism length of side is the mm of 1 mm ~ 60, thick Spend for the mm of 1 mm ~ 60.
- 7. the total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 1,2,3,4,5 or 6, its feature It is, described input path also includes being used to produce the polarizer for determining polarization state；The polarizer is located at monochromatic light Between device and light polarization modulator.
- 8. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 7, it is characterised in that described Input path also includes being used for the phase-shifter for introducing adjustable phase change；Any position of the phase-shifter between the polarizer and prism Put.
- 9. the total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 2,3,4,5 or 6, its feature exist In the ranges of incidence angles of described input path is 30 ° ~ 85 °.
- 10. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 9, it is characterised in that described Translation stage for driving stepper motor, DC servo motor drive motor machine translation stage；Described biochip it is transparent Substrate is the slide of slide, the slide of plating metal on surface film or surface gold-plating metal particles.
- 11. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 10, it is characterised in that described Metal film be golden film, silverskin, chromium film or metallized multilayer film；Described metallic particles is gold grain, Argent grain or metal mixed Particle.
- 12. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 11, it is characterised in that described Thickness of metal film scope be the nm of 10 nm ~ 80；The particle size range of described metallic particles is the nm of 1 nm ~ 80.
- 13. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 11, it is characterised in that described Metal film or metallic particles be located at slide lower surface or in prism lower surface.
- 14. the total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 1,2,3,4,5,6,8 or 10, Characterized in that, the reflected light path of described detection reflection light polarization state includes analyzer and photodetector.
- 15. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 14, it is characterised in that described Analyzer be devating prism, reflective polarizer, scatter-type polarizer or dichroism linear polarization；Described photoelectricity is visited Survey device is linear photodiode, photodiode array, charge coupling device imaging sensor or CMOS half Conductor imaging sensor.
- 16. the total-reflection type oblique incident ray difference in reflection according to claim 1,2,3,4,5,6,10,11,12 or 15 is scanned into As device, it is characterised in that described data acquisition unit includes data collecting card and data processor；Wherein, the data Processor is the data processor of lock-in amplifier, frequency spectrum analyser, oscillograph or application Fourier analysis algorithm.
- 17. total-reflection type oblique incident ray difference in reflection scanned imagery device according to claim 16, it is characterised in that：Also wrap Include the liquid-treatment unit of cushioning liquid pump, sample solution pump, selector valve and switching valve composition；Wherein, sample fluid pump and One selector valve is connected, and first choice valve is connected with switching valve, and switching valve is connected with the second selector valve, the second selector valve and fluid cavity Connection, cushioning liquid pump are connected with switching valve.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107356560A (en) * | 2017-07-20 | 2017-11-17 | 复旦大学 | Total-reflection type oblique incident ray difference in reflection scanned imagery device and its application method |
| CN110261317A (en) * | 2019-06-17 | 2019-09-20 | 西安理工大学 | A kind of measuring system and method for Mueller matrix spectrum |
-
2017
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107356560A (en) * | 2017-07-20 | 2017-11-17 | 复旦大学 | Total-reflection type oblique incident ray difference in reflection scanned imagery device and its application method |
| CN107356560B (en) * | 2017-07-20 | 2023-11-24 | 复旦大学 | Total reflection type oblique incident light reflection difference scanning imaging device and using method thereof |
| CN110261317A (en) * | 2019-06-17 | 2019-09-20 | 西安理工大学 | A kind of measuring system and method for Mueller matrix spectrum |
| CN110261317B (en) * | 2019-06-17 | 2021-11-16 | 西安理工大学 | Measurement system and method for Mueller matrix spectrum |
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