CN110137792A - Multi-core optical fiber cell laser with stretch function - Google Patents
Multi-core optical fiber cell laser with stretch function Download PDFInfo
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- CN110137792A CN110137792A CN201910396363.4A CN201910396363A CN110137792A CN 110137792 A CN110137792 A CN 110137792A CN 201910396363 A CN201910396363 A CN 201910396363A CN 110137792 A CN110137792 A CN 110137792A
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
- G02B6/02—Optical fibres with cladding with or without a coating
- G02B6/02042—Multicore optical fibres
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
- G02B6/24—Coupling light guides
- G02B6/26—Optical coupling means
- G02B6/262—Optical details of coupling light into, or out of, or between fibre ends, e.g. special fibre end shapes or associated optical elements
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
- G02B6/24—Coupling light guides
- G02B6/26—Optical coupling means
- G02B6/264—Optical coupling means with optical elements between opposed fibre ends which perform a function other than beam splitting
- G02B6/266—Optical coupling means with optical elements between opposed fibre ends which perform a function other than beam splitting the optical element being an attenuator
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- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21K—TECHNIQUES FOR HANDLING PARTICLES OR IONISING RADIATION NOT OTHERWISE PROVIDED FOR; IRRADIATION DEVICES; GAMMA RAY OR X-RAY MICROSCOPES
- G21K1/00—Arrangements for handling particles or ionising radiation, e.g. focusing or moderating
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
- H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
- H01S3/05—Construction or shape of optical resonators; Accommodation of active medium therein; Shape of active medium
- H01S3/08—Construction or shape of optical resonators or components thereof
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
- H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
- H01S3/09—Processes or apparatus for excitation, e.g. pumping
- H01S3/091—Processes or apparatus for excitation, e.g. pumping using optical pumping
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- Investigating Or Analysing Materials By Optical Means (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
The present invention is to provide a kind of multi-core optical fiber cell Optical Maser System with stretch function.It is somebody's turn to do " optical fiber-cell " laser to be mainly made of following four part: (1) there is new structural multi-core optical fiber, which, at double angular cone truncated cone-shapeds of rotational symmetry, is prepared into optical fiber optical tweezers by rubbing down；(2) miniature optical resonant cavity, the intracavitary gain media for optical amplifier function；(3) the photodynamic light source of cell capture and gain media excitation light source be can provide；(4) the detecting light spectrum instrument of cell output laser.The output spectrum of cell interior microsphere optical resonant cavity is very sensitive to the variation that the environmental physics parameter such as cell interior cytosol is faint, can be measured by the amplification laser signal that multicore tapered optical fiber exports.The present invention can be used for unicellular capture, the measurement of cell laser spectrum, can be widely used for Manipulation of single cells, sensing, measurement and analysis technical field.
Description
(1) technical field
The present invention relates to a kind of multi-core optical fiber cell Optical Maser System with stretch function, can be used for cell and catches
Obtain, cell laser spectrum measurement and cell laser self assembly, be particularly suitable for Manipulation of single cells, measurement and analytical technology neck
Domain.
(2) background technique
Nineteen sixty American scientist T.H. plum is graceful et al. successfully to create First ruby crystal laser in the world,
A. Jia Wen in 1961 et al. successfully develops He-Ne laser, and R.N. Hall in 1962 et al. develops gallium arsenide semiconductor laser
Device.The birth of laser indicates the direction of the launch, phase, frequency and the polarization etc. of the capable multiple photons of regulation of people, makes one
Higher level has been reached to the understanding of light and application.Laser shows beyond imagination in micromation and cross discipline direction
Application value, therefore this field of light stream body laser is just come into being.Light fluid is respectively unique in conjunction with optics and fluid
Advantage and the novel research field of a multi-crossed disciplines that is formed, concept mentioned in 2003 by university, California Institute of Technology
Out, living organism has very wide because there are natural liquid environments in fields such as biomedical diagnostics, sensor measuring and imagings
General application prospect.
Cell laser is a kind of special light stream body laser (laser and optoelectronics progress, cell Laser Study
Progress and application summary, 2018,55:120001), the liquid environment of organism existence can be simulated in vitro or directly in life
In object, the laser output of cell is realized under the excitation of outside energy.It is common compared in current biomedical every field
The fluorescence signal detection method arrived has its own unique advantage by the way of laser signal detection.Firstly, laser signal
It is the spontaneous emission light that excited radiation light is different from fluorescence signal, it is good being had after the signal of resonant cavity amplification feedback
Directionality；Secondly, the signal energy of work particle output is much higher than fluorescence signal when driving source laser signal is higher than threshold value,
So the resolution ratio of laser signal detection and sensitivity can also be much higher than fluorescence detection, also, laser signal output spectrum line width
Spectrum width is extremely narrow compared with the fluorescence spectrum of luminescent material, is conducive to be timely responded in sample detection process in this way.Cell swashs
Common gain media is generally fluorescent material in light device, such as fluorescin (NATURE PHOTONICS, Single-cell
Biological lasers, 2011,5:406-410), fluorescent dye (Bio-switchable optofluidic lasers
Based on DNA Holliday junctions, 2012,12 (19): 3673-3675), fluorescein, quantum dot, vitamin,
And fluorescence resonance energy transfer equity, gain media and cell are subjected to organic combination, absorb the increasing emitted after excitation energy
Beneficial signal amplifies through the continuous oscillatory feedback of optical resonator, when gain is greater than intracavitary total losses, will form laser output.
In June, 2001, Gather of Harvard University et al. allow human embryonic kidney cells to launch laser signal (NATURE
PHOTONICS, Single-cell biological lasers, 2011,5:406-410), in device excitation light source need by
Image enhancement system focusing makes hot spot be contracted to individual cells size, and it is bigger using two panels high reflection mirror to bond out a space
In the Fabry-Perot cavity of cell size, to limit cell in the position of excitation light, so the device volume is huge
Greatly, the direction and position of spatial excitation light are not easy to adjust to unicellular, and the method that can only be limited by free surrounding space is come
Capture cell.2015, the Humar et al. of medical college, Harvard University had developed a plurality of cells based on Whispering-gallery-mode microcavity and swashs
Light device (NATURE PHOTONICS, Intracellular microlasers, 2015,9:572-576), it was demonstrated that natural
Into the cell can also realize laser export, artificially in the cell be placed in a regular circle shapes fat drips as Whispering-gallery-mode, it is defeated
Signal is coupled to spectral detector through 200 μm of core diameter of multimode fibre out, but the device volume is larger, and receives signal and made
Optical fiber is thicker, due to micro- manipulation function such as can not precisely capture to cell, so that this behaviour of excitation beam irradiating cell
Work becomes inaccurate, and the micro-displacement of cell in a liquid, which will lead to excitation light beam, can not accurately be coupled into fat drips, makes to increase
Beneficial signal can not continuously enhance, while also increase the operation difficulty of experiment.
Surface force about optical induction leads to the capture and stretching of cell, and the common method to cell tensile has, and leads to
Crossing the transmitting of optics stretcher combination microfluid can be such that single suspension cell deforms by the surface force of optical induction, pass through two beams
Contrary spatial light, allow cell in microfluidic channel captured and deformed by divergent laser beam (Biophys,
The optical stretcher:a novel laser tool to micromanipulate cells,81:767–784,
2001).Other methods are connect in addition, passing through the processed silicon oxide pellets of protein coating with two by erythrocyte,
In bead it is fixed on a glass, another bead is captured by optical tweezer, and in the moving process of ligh trap, bead is with optical tweezer
Movement and move, to achieve the effect that erythrocyte is stretched (Acta Mater, Large deformation of
living cells using laser traps,52,1837–1845,2004).In addition to this also have directly using glass or
The tip of metal and cell contact are measured the viscosity of cell by the stretching of the distance between two tips and curvature, equally may be used
To carry out stretched operation (Biophysical Journal, Creep Function of a Single Living to cell
Cell,88:2224-2233,2005).These methods include the equipment of two opposite directions, including photodynamic and machinery moves
Power, contact or non-contacting stretched operation are carried out to the two sides of cell, wherein can also require micro-fluidic due to light source etc.
The other equipment such as channel guarantee that the cell being stretched can only be passed through always in the environment easily survived by spatial light
Microfluidic channel operates, it is proposed by the invention based on the cell laser of novel optical fiber structure by cell capture, stretching, swash
The functions such as hair and reception integrate, and greatly reduce the number and size of required instrument, reduce experimental procedure,
Reduce experiment difficulty.
The patent of invention of Patent No. CN201510295509.8 proposes a kind of tunable liquid cell laser, the patent
It is middle that two optical fiber optical tweezers is needed to carry out capture operation to cell simultaneously, and received using one end optical fiber output opposite direction other end optical fiber
Mode collecting signal light；The patent of invention of Patent No. CN201510267391.8 proposes a kind of drop Whispering-gallery-mode laser
Device and preparation method thereof needs that optical coupling will be inputted by way of single mode optical fiber and toroidal cores optical fiber fused tapering in the patent
Into in toroidal cores, drop, which also needs to contact with micro-nano fiber, to go out signal optical transport；Patent No.
The patent of invention of CN201510271055.0 proposes a kind of multi-wavelength drop laser, due to needing to multiple drops in the patent
Excitation-detection is carried out, identical with a upper patent, each drop is required to contact output, this method with a micro-nano fiber
Undoubtedly increase the difficulty of device, it is well known that the size of micro-nano fiber only has several microns, is highly prone to the shadow of external environment
It rings, and is difficult to keep the cleaning of optical fiber surface for a long time, and need the linear arrangement of multiple drops in the patent, also just mean
Need multiple micro-nano fiber the distribution of line shape, since the size of drop is smaller, this also proposes high requirement to experimental implementation.
The patent of invention of Patent No. 201810169543.4 proposes the multi-functional spectrometer of Living single cell based on coaxial double wave guiding fiber,
The cell glimmer hand being previously mentioned in the patent and optical fiber used in this patent capture cell principle are close, be equally with multicore into
Row capture, but apparatus structure and central core function are had nothing in common with each other, and the present invention not only enriches the structure of optical fiber, also increases light
Fine various new function, while the processing structure of optical fiber optical tweezers optical fiber end is changed again, and then changes the capture to cell
The position of light field keeps the operability of experiment stronger.It is proposed by the present invention that there is drawing based on novel compared with the above patent of invention
The multi-core optical fiber cell Optical Maser System of function is stretched, the new structure of optical fiber includes a middle fiber core and multiple and different structures point
Multiple functions such as cell capture, the stretching of cell posture, the excitation of gain substance and optical signal reception are integrated in together by the fibre core of cloth
In one optical fiber, and optimize optical fiber optical tweezers to the capture light field of cell, the invention by the analysis detection to Living single cell with
And to the essential laws for disclosing vital movement, provide more reliable scientific basis.
The present invention proposes a kind of novel multi-core optical fiber cell laser system with stretch function under background above
System.On the one hand it can transmit different optical bands by multiple fibre cores, thus the distribution completed the capture of cell, operate light field
With the excitation of cell laser, therefore have light field regulation and excitation characteristic；On the other hand, luminous intensity is captured by regulation, it can
To adjust ligh trap distribution intensity, so as to control the degree being stretched, complete excitation light path with microresonator accurately right
It connects.This device uses novel multi-core optical fiber, has the characteristics of multi-pass Highgrade integration, with the volume of very little and flexible
Flexible nature provides important multi-functional work for the exploration and research of the life science problem of the Living single cell similar to 7
Tool, the present invention is a kind of new laser under subject crossing fusion development trend, therefore is had a very important significance and valence
Value.
(3) summary of the invention
The purpose of the present invention is to provide a kind of multi-core optical fiber cell Optical Maser System with stretch function, can be used for list
Cell capture, the measurement of cell laser spectrum.
A kind of multi-core optical fiber cell Optical Maser System with stretch function, should " optical fiber-cell " laser mainly by
Following four part composition: (1) having new structural multi-core optical fiber, which is bored by rubbing down at double angles of rotational symmetry
Body truncated cone-shaped, is prepared into optical fiber optical tweezers；(2) miniature optical resonant cavity, the intracavitary gain media with optical amplifier function can be with
It is distributed in ball, ball is outer or spherical shell surface layer；It (3) include that can provide the photodynamic light source of cell capture and wave that wavelength is 980nm
Grow the gain media excitation light source in 460-670nm；(4) the detecting light spectrum instrument of cell output laser.In the Optical Maser System:
Capture light beam is drawn by standard single-mode fiber 6 from capture light source 2, is divided via 1 × N coupler 3 for two-way light, is passed through 4-2 respectively
Multi-core optical fiber 9 is respectively enterd after to 4-N attenuator and multi-core optical fiber splitter 8 again except in other fibre cores of intermediate core.Swash
It encourages light beam and is drawn by standard single-mode fiber 6 from excitation light source 1, enter multi-core optical fiber splitter by attenuator 4-1 and circulator 5
8, subsequently into the middle fiber core of multi-core optical fiber 9.
The liquid of cell is filled in sample cell and is stablized on objective table 11, in the sample cell that optical fiber optical tweezers 10 are immersed in, is used
In realizing multi-core optical fiber probe to cell capture and manipulation, accurate displacement operation process passes through image enhancement system 12, CCD13
Real time imagery is carried out with the image-forming module that computer 14 forms.At the same time, the cell laser signal detected passes through three end ring
Shape device 5 enters spectrometer 7 and receives.Cell in liquid is caught by the optical fiber optical tweezers 10 with rotational symmetry cone truncated cone-shaped optical fiber end
It obtains, manipulation is combined by the force trapping of optical fiber optical tweezers multi-fiber core, is realized to the adjustment of cell position and the stretching of posture, so that in
Between the exciting light that is emitted of fibre core accurately docked with the completion of resonance microballoon, meet to microsphere resonator offer excitation light source and defeated
The condition of resonance to be detected enhancing fluorescence signal out, to be self-assembled into as novel " optical fiber-cell " laser.?
In the system structure of above-mentioned " optical fiber-cell " laser, plurality of waveguide, which is played, carries out the capture of light power and stretching to cell
Effect, and middle fiber core waveguide provides an exciting light to captured cell, the exciting light of sending and intracellular quilt
Microballoon after stretching is coupled, to realize to the resonant excitation of microballoon and the output of laser signal, is completed to cell interior
The sensing and measurement of the parameters such as cytosol refractive index minor change, as shown in Figure 1.
Multi-core optical fiber 9 of the present invention has the side core wave of a middle fiber core waveguide and multiple and different distribution of shapes
It leads.Plurality of core waveguide is used for transmission capture light beam and precisely manipulation adjustment cell posture, intermediate core are then used for transmission
Excitation beam, be as shown in Figure 2 multi-core optical fiber structure and index distribution schematic diagram and each core waveguide in be passed through
The classification of light.
Light beam is captured to inject in multiple fibre cores of multi-core optical fiber 9 by coupler 3 and attenuator 4-1 to 4-N.The band of light
Beam is used for the capture of cell, and method is to prepare the reflection of the rotational symmetry as made of fine gtinding using the optical fiber end of multi-core optical fiber
Multi-angle frustum structure, as optical fiber optical tweezers 10, the refraction for multi-fiber in-core transmitting beam is assembled, and is formed light and is captured potential well.
The capture light beam that multi-core optical fiber transmits in other fibre cores in addition to middle fiber core can carry out reflection focusing by the frustum cone structure,
To realize deeper capture potential well, it to be used for cell capture.Capture and excitation are stablized to cell in order to realize, light can be passed through
Fine end rubbing down technology prepares optical fiber optical tweezers, such as the multi-angle cone frustum cone structure of rotational symmetry, as shown in Figure 4.In order to meet folding
Convergence is penetrated, frustum base angle needs to meet: α < arcsin (n1/n2), n1For liquid environment refractive index locating for cell, n2For fibre core refraction
Rate.In order to increase the distance between focus, the range for making cell that can be stretched is bigger, for this purpose, can be by changing rotational symmetry
The method of cone frustum cone structure realize.Multi-angle cone frustum cone structure is processed into section cone frustum cone structure (Fig. 3 (a))
(Fig. 3 (b)) can further increase the spacing of two focus points by the structure change of section, this can increase grasping for cell
Make range.
The optical gradient forces gesture issued using the optical fiber optical tweezers (shown in Fig. 4) of the multi-angle cone frustum cone structure after processing
During trap captures cell, each waveguide can regulate and control light intensity by attenuator independent, can not only capture thin
Born of the same parents, and can be realized stretching manipulation of the cell on the radial Z of position (X, Y, Z), the process of this manipulation can be by aobvious
The ccd image of micro mirror is observed to feed back its adjustment effect roughly, when optical power becomes larger, the position of nearly two beam focus of cell
Stress becomes larger, and cell is integrally stretched deformation, to further change the optical power size of each light beam according to deformation.Quilt
For the stress condition of the cell of capture as shown in figure 5, the focus for capturing light beam in fibre core corresponds to the bottom of gradient force potential well, XY is flat
F on face1-F4Reach equilibrium state, and the light-field capture power F issued with each core5And F6Mutually balance is to complete the steady of cell
It is fixed to stretch.
Light beam is motivated to inject the middle fiber core of multi-core optical fiber 9 by attenuator 4-1, circulator 5 and multi-core optical fiber splitter 8
It is interior.The excitation beam transmitted in the middle fiber core of multi-core optical fiber can directly pass through the frustum cone structure end face, realize captured thin
The excitation of born of the same parents' laser, method are as follows: after the beam-capturing that cell is issued by multi-core optical fiber is lived, pass through two light focus point energy
It adjusts, microballoon is drawn into micro- elliposoidal by uneven distribution trapping stiffness, and when excitation light excitation, which can make
For an optics Fabry-Perot micro chamber, the laser signal after excitation is limited in the resonant cavity of micro-nano magnitude.It can also manage
The both ends of Xie Weiwei ellipsoid long axis are equivalent to the anti-hysteroscope of height that two sides is placed in parallel, optical signal round-trip transmission between hysteroscope,
The light roundtrip that near axis is propagated forms standing wave, is formed outside laser output cavity by feedback light amplification.But due to generally existing
Two being placed in parallel for hysteroscope are not absolute stabilities in experiment, extremely to the microvibration of ambient enviroment or other external conditions
Sensitivity, if small angular deflection occurs for resonant cavity, then the optical signal of round-trip transmission pole after multiple reflections in resonant cavity
Outside easy spill cavity, so as this low threshold laser of cell laser needs a metastable Fabry-Perot micro chamber,
For micro- ellipsoid because the optical field distribution by centrosymmetric structure manipulates, the meeting after being stretched becomes the elliposoidal of rule, can
The theoretical calculation of stable condition is carried out in a manner of through abcd matrix:
The stability condition for needing to meet is
Intracavitary in the cell laser resonator based on Fabry-Perot-type cavity, light will pass through hysteroscope and cell twice respectively,
It is in intracavitary incident ray transmission matrix M1For
Reflection light ability transmission matrix M2For
In above formula, R is the stability condition that cell radius calculates resonant cavity, ncellFor the effective refractive index of intracellular matter, n0
For cell external world ambient refractive index.Cell laser exports faint laser signal, and threshold value is lower than traditional laser, this
Meet the application demand in biologic medical field from now on, so threshold value is an important parameter for cell laser.Generally
The there is provided gain of unit length fluorescent material is
In formula, N is the molecular concentration of fluorescent material, and τ is fluorescence lifetime, and c is the spread speed of light in a vacuum, σssFor laser
Absorption cross-section corresponding to wavelength.Wherein,
In formula, n is the refractive index of laser medium, and J (z) is variation function of the pump intensity in z-axis direction, σ0For pump wavelength institute
Corresponding absorption cross-section, h υ are photon energy, and E (λ) is the line shape function of spontaneous radiation, and
φ is quantum yield in formula.The primary signal light light intensity of intracavity round trip can pass through
It acquires.When reaching threshold value, light intensity when intracavity round trip primary light intensity is equal to initial calculates cell in this way
The threshold value of laser, but in an experiment often by the matched curve of measurement data come threshold value.Fig. 6 is that Fabry-Perot is humorous
The mode of vibration chamber microballoon operation principle schematic diagram, this limitation light field can make intracavitary luminous intensity very high, can effectively improve pumping
It transports efficiency and largely can satisfy the application demand in cell biology to greatly reduce laser threshold.
Multi-core optical fiber splitter 8 involved in it can be regarded as that outgoing beam can be assigned to multiple and different light splitting branches
In, and the device that can be coupled into each fibre core of multi-core optical fiber, wherein each light splitting branch again can be single by attenuator 4
Solely control.
The operation principle schematic diagram of multi-core optical fiber cell Optical Maser System with stretch function, as shown in Figure 1, in order to full
The demand of the various sensing measurements of foot, the present invention can replace microballoon with single biological cell, to can realize based on multi-core optical fiber
Cell laser.
The present invention at least has obvious advantage below:
(1) a kind of cell laser is proposed.Other slender cytoplasm lasers having proposed are compared to, it is proposed by the present invention
Laser have the characteristics that it is noninvasive, real time laser spectral detection may be implemented.
(2) unicellular capture technique, stretching and cell laser are integrated in same root multi-core optical fiber by the present invention, energy
Eucaryotic cell structure and chemical composition information abundant is provided.Therefore the present invention can realize single celled point comprehensive, multi-functionally
Analysis.
(3) multiple operating functions are integrated within an optical fiber by optical fiber probe proposed by the invention, and optical fiber probe
Have the feature that integrated level is high, operating flexibility is high, can be realized quickly analyzing in body for Living single cell.
(4) Detailed description of the invention
Fig. 1 is the schematic device with the multi-core optical fiber cell Optical Maser System of stretch function.
Fig. 2 is the class of be passed through light in the structure and index distribution schematic diagram and each core waveguide of multi-core optical fiber
Not.
Fig. 3 is optical fiber cone truncated conical shape prioritization scheme: optical fiber cone rotary table before (a) optimizing；(b) optical fiber cone after optimizing
Rotary table.
Fig. 4 is the rotational symmetry multi-angle cone frustum cone structure schematic diagram at the long and slender end of multi-core optical.
Fig. 5 is microballoon stress diagram when multi-core optical fiber brings out the two light beams combination light field penetrated.
Fig. 6 is to receive laser signal map schematic diagram according to Fabry-Perot resonance microcavity working principle.
Fig. 7 is the schematic device with five core fibre cell Optical Maser Systems of stretch function.
Fig. 8 is illustrated based on laser measurement working principle of the five core fibre cell lasers of the distribution of line shape to monomer living cells
Figure.
Fig. 9 shows the laser measurement working principle of monomer living cells based on seven core fibre cell lasers of Triangle-Profile
It is intended to.
(5) specific embodiment
It is known that cell biology is still the important subject in life science, it is support biotech development
Basis.Although the working mechanism to cell on general levels does not obtain the mankind at present it was found that cell more than 300 years
One is obtained completely clearly to recognize.Cell biology be from the different structure level of cell come study cell vital movement base
This rule.With modern science and technology achievement and method, concept, the information of cell interior is disclosed on a cellular level, is cell
One of the important channel that biological information obtains.
Living single cell technology is the forward position of biology at present technology, and many new biology letters can be provided to scientist
Breath, can not only examine over the conclusion of classical way, but also it can be found that many new rules.For example, single cell technology is first
Scientist can be first allowed to check whether really there is cell average value index, that is to say, that whether past many cells research method
How is the levels of precision of genuine reliable and this tradition research technology.In addition, Single cell analysis method can provide it is very rich
Information, be sometimes not expect or information that the past is covered by statistical result.Unicellular research can not only make up
The important information for being blanked and omitting caused by due to group's cell sample is removed, keeps the result of " group is learned " research more objective
With it is comprehensive, and be possible to obtain still not found new phenomenon and new rule in life science, therefore, for life science
Research have especially important meaning.
For decades, researcher is mainly to cell mass deployment analysis.Carrying out the important prerequisite studied in this way is people
The individual cells for thinking to constitute these cell masses (such as normal tissue cell and tumour cell), are almost homogeneous or the same
, eligible result is all the average value of these cell group characters.It is recent years, slender with the announcement of cell heterogeneity phenomenon
Born of the same parents' analytical technology is gradually valued by people.However single cell analysis is faced with many problems.Most challenging is spirit
Sensitivity is difficult to meet demand, is either directed to single specificity macromolecular, or carry out analysis of molecules in group level, all deposits
It is few in unicellular extraction object amount and be difficult to analyze, even can be described as the difficulty that can not be completed.
Due to the limitation of sensitivity and sample volume etc., common life science is mainly with a large amount of cell
Research object.But there is significant microheterogeneity (heterogeneities) between the Different Individual of allogenic cell, based on a large amount of thin
The experimental result of born of the same parents is difficult to reflect the rule of the vital movement on individual cell level.Therefore, the analysis based on Living single cell will
The essence and rule that vital movement is disclosed on deeper level, provide more to probe into cause, development and the treatment of major disease
Reliable scientific basis.
Below by taking the multi-core optical fiber cell Optical Maser System with stretch function as an example, the present invention is carried out specifically
It is bright.
Embodiment 1: laser measurement of the cell laser of five core fibres based on the distribution of line shape to monomer living cells:
Fig. 7 is the schematic device with the multi-core optical fiber cell Optical Maser System of stretch function, the Optical Maser System
In: capture light beam is drawn by standard single-mode fiber 6 from capture light source 2, is divided via 1 × N coupler 3 for two-way light, is passed through respectively
Multi-core optical fiber 9 is respectively enterd after 4-2 to 4-N attenuators and multi-core optical fiber splitter 8 again except in other fibre cores of intermediate core.
Excitation light beam is drawn by standard single-mode fiber 6 from excitation light source 1, enters multi-core optical fiber branch by attenuator 4-1 and circulator 5
Device 8, subsequently into the middle fiber core of multi-core optical fiber 9.Liquid containing cell is filled in sample cell and is stablized in objective table 11
On, in the sample cell that optical fiber optical tweezers 10 are immersed in, for realizing multi-core optical fiber probe to cell capture and manipulation, accurate displacement behaviour
Make process and real time imagery is carried out by the image-forming module that image enhancement system 12, CCD13 and computer 14 form.At the same time,
The cell laser signal detected enters spectrometer 7 by three end circulators 5 and receives.Cell in liquid is by being had rotation
The optical fiber end optical fiber optical tweezers 10 of symmetrical cone truncated cone-shaped capture, and combine behaviour by the force trapping of the cone multi-fiber core of optical fiber optical tweezers
Control is realized to the adjustment of cell position and the stretching of posture, so that exciting light and resonance microballoon that middle fiber core is emitted are completed
Accurately docking meets and provides excitation light source to microsphere resonator and export the condition of resonance enhancing fluorescence signal to be detected,
To be self-assembled into as novel " optical fiber-cell " laser.In the system structure of above-mentioned " optical fiber-cell " laser
In, plurality of waveguide is played the role of carrying out the capture of light power and stretching to cell, and middle fiber core waveguide is to captured
Cell provides an exciting light, and the exciting light of sending is coupled with the microballoon after intracellular be stretched, to realize pair
The resonant excitation of microballoon and the output of laser signal, complete to the sensings of the parameters such as cell interior cytosol refractive index minor change with
Measurement.
As shown in figure 8, cell here selects HEK293 human embryonic kidney cells 15, this cell be commonly used in biology into
The mammalian cell of row transfection, cell dia are 13.8 μm, and gain media green fluorescent protein molecule is had with cell
Machine integration.When system works, the wavelength of capture light beam 17 uses 980nm, and excitation 18 wavelength of light beam uses 480nm, two-beam point
It is not passed through in middle fiber core and other fibre cores of multi-core optical fiber 9.The fibre core light beam that 980nm capture light is passed through is realized in centrum rotary table
Light reflection, is converged to ligh trap at from fiber end face a distance, by adjusting the light intensity in fibre core respectively to the thin of capture
Born of the same parents carry out precisely manipulating adjustment cell posture again.Middle fiber core is passed through the excitation light 18 of 480nm, when the position that cell is adjusted is full
When being enough to the concussion condition of the micro- ellipsoid 16 of gain substance in cell 15 and the issued exciting light of middle fiber core waveguide, gain media quilt
Laser signal caused by exciting constantly amplifies through microsphere resonator, when gain is greater than intracavitary total losses, swashs to be formed
Light output, laser signal 19 is received by middle fiber core return where excitation light beam, then is transmitted to circulator 5, finally by
Spectrometer 7 completes feedback path, obtains cell laser light spectrogram.
Embodiment 2: laser measurement of the cell sensor of seven core fibres based on Triangle-Profile to monomer living cells:
The system is identical as the cell sensor device composition of five core fibre of the distribution of line shape, due to the quantity and distribution of fibre core
It changes, the capture light beam 17 and excitation beam 18 in system enter multi-core optical fiber splitter 8 by 1 × 6 coupler 3 respectively
In, it is injected into corresponding fibre core respectively, wherein fibre core bcdefg is capturing function fibre core, and what is injected is capture light beam
17, fibre core a are arousal function fibre core, and what is injected is excitation beam 18.Here cell selects HEK293 human embryonic kidney cells 15,
When system works, the wavelength of capture light beam 17 uses 980nm, and excitation 18 wavelength of light beam uses 480nm, except other of middle fiber core
Fibre core can reach the function for carrying out precisely manipulating adjustment cell posture again to the cell captured by individually controlling attenuator 4
Can, while middle fiber core is used to activated cell signal light.Intracellular laser signal 19 passes through intermediate fine where excitation light beam
It returns and is received in core, then be transmitted to circulator 5, complete feedback path finally by spectrometer 7, obtain cell laser spectrum
Figure, as shown in Figure 9.
Claims (7)
1. a kind of multi-core optical fiber cell Optical Maser System with stretch function, should " optical fiber-cell " laser mainly by with
Lower four parts form: (1) having new structural multi-core optical fiber, the optical fiber end is by rubbing down at double angular cones of rotational symmetry
Truncated cone-shaped is prepared into optical fiber optical tweezers；(2) miniature optical resonant cavity, the intracavitary gain media with optical amplifier function, Ke Yifen
Cloth is in ball, outside ball or spherical shell surface layer；It (3) include that can provide the photodynamic light source of cell capture and gain media excitation light source；
(4) the detecting light spectrum instrument of cell output laser.
2. the multi-core optical fiber cell Optical Maser System according to claim 1 with stretch function.The Optical Maser System
In: capture light beam is drawn by standard single-mode fiber 6 from capture light source 2, is divided via 1 × N coupler 3 for the road N light, is passed through 4- respectively
Multi-core optical fiber 9 is respectively enterd after 2 to 4-N attenuator and multi-core optical fiber splitter 8 again except in other fibre cores of intermediate core.Swash
It encourages light beam and is drawn by standard single-mode fiber 6 from excitation light source 1, enter multi-core optical fiber splitter by attenuator 4-1 and circulator 5
8, subsequently into the middle fiber core of multi-core optical fiber 9.The liquid of cell is filled in sample cell and stablizes the optical fiber on objective table 11
In the sample cell that optical tweezer 10 is immersed in, for realizing multi-core optical fiber probe to cell capture and manipulation, accurate displacement operation process
By image enhancement system 12, the image-forming module of imaging system (CCD) 13 and the composition of computer 14 carries out real time imagery.It is same with this
When, the cell laser signal detected enters spectrometer 7 by three end circulators 5 and receives.Cell in liquid is by being had
The optical fiber end optical fiber optical tweezers 10 of rotational symmetry cone truncated cone-shaped capture, and are combined by the force trapping of the cone multi-fiber core of optical fiber optical tweezers
Manipulation is realized to the adjustment of cell position and the stretching of posture, so that exciting light and resonance microballoon that middle fiber core is emitted are complete
At accurate docking, meets and provide excitation light source to microsphere resonator and export the item of resonance enhancing fluorescence signal to be detected
Part, to be self-assembled into as novel " optical fiber-cell " laser.In the system knot of above-mentioned " optical fiber-cell " laser
In structure, plurality of waveguide is played the role of carrying out cell the capture of light power and stretching, and middle fiber core waveguide is to captured
Cell provide an exciting light, the exciting light of sending is coupled with the microballoon after intracellular be stretched, to realize
The sensing to parameters such as cell interior cytosol refractive index minor changes is completed in the output of resonant excitation and laser signal to microballoon
With measurement.
3. the multi-core optical fiber cell Optical Maser System according to claim 2 with stretch function.Involved in system
Multi-core optical fiber can be a kind of with triangle it is characterized in that: the optical fiber can be a kind of five core fibres with the distribution of line shape
Perhaps 13 core fibres are also possible to a kind of nine core fibres or 13 cores with the distribution of square diamond shape to seven core fibres of distribution
Optical fiber more can be a kind of 13 core fibres with annular spread or 17 core fibres etc..
4. the multi-core optical fiber cell Optical Maser System according to claim 2 with stretch function.Involved in system
A kind of miniature optical resonant device has elasticity it is characterized in that: the geometry of the resonator is center symmetric body, and stress is variable
Shape, and certain gain media is contained in inside.Micro- shape resonator shape is preferential selection with microspheroidal.
5. the multi-core optical fiber cell Optical Maser System according to claim 2 with stretch function.Involved in system
Microresonator can be certain unicellular spherical shape, intracellular existing certain biomone or the intracellular rule elasticity of merging
Spheroidal particle.
6. the multi-core optical fiber cell Optical Maser System according to claim 2 with stretch function.Involved in system
Two focuses that multiple fibre cores are formed form two ligh traps, and microresonator stress is stretched, and become elliposoidal from spherical shape.
7. a kind of novel " optical fiber-cell " laser self-assembling method, it is characterized in that:
(1) static capture is carried out to cell using multiple core waveguides；
(2) the light force trapping that microresonator is issued by multiple fibre cores stretches, and keeps equilibrium state, is deformed into from spherical shape ellipse
Spherical shape forms a Fabry-Perot micro chamber.
(3) microresonator is accurately coupled with the exciting light that middle fiber core waveguide issues, according to Fabry-Perot micro chamber principle,
It realizes to the resonant excitation of resonator and the output of laser signal.
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