CN202748365U - Biochemical microcantilever array sensing device based on acousto-optic modulator - Google Patents
Biochemical microcantilever array sensing device based on acousto-optic modulator Download PDFInfo
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- CN202748365U CN202748365U CN 201220188581 CN201220188581U CN202748365U CN 202748365 U CN202748365 U CN 202748365U CN 201220188581 CN201220188581 CN 201220188581 CN 201220188581 U CN201220188581 U CN 201220188581U CN 202748365 U CN202748365 U CN 202748365U
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Abstract
A biochemical microcantilever array sensing device based on an acousto-optic modulator comprises a laser, an acousto-optic modulator, a biochemical reaction tank, a microcantilever array, a photoelectric position-sensitive detector (PSD) and a monitoring unit, wherein the acousto-optic modulator is arranged on a light path of a collimated laser beam generated by the laser; the microcantilever array is arranged inside the biochemical reaction tank; the microcantilever array is arranged on a light path of emergent light of the acousto-optic modulator; a target surface of the photoelectric position-sensitive detector (PSD) is arranged on a light path of reflected light of the microcantilever array; a signal output end of the photoelectric position-sensitive detector (PSD) is connected with a signal input end of the monitoring unit; the acousto-optic modulator comprises an acousto-optic medium and a piezoelectric transducer; the piezoelectric transducer receives a carrier frequency signal, generates ultrasonic wave with the same frequency and transmits the ultrasonic wave into the acousto-optic medium; the collimated laser beam passes through the acousto-optic medium and is refracted to obtain the emergent light. The biochemical microcantilever array sensing device based on the acousto-optic modulator is simple in structure of a detecting light path, easy to implement, small in volume, light in weight and convenient to move.
Description
Technical field
The utility model belongs to or relates to the biochemical sensitive technical field, and its practical novel creation can specifically be applied to monitoring and the detection in the fields such as food security, environmental pollution, biomedicine, scientific research and the manufacturing.
Background technology
Micro-cantilever (all claiming later on little beam) the biochemical sensitive technology that detects based on surface stress is a kind of emerging sensing technology that in recent years occurs, its principle is: probe (antigen or antibody) molecule is fixed (modification) on the Gold plated Layer of little beam one side with direct or indirect mode, when the target molecule in the detected sample liquid and the probe molecule generation specific reaction on little beam gold surface, little beam surface stress is changed, thereby cause little beam deformed, detect the process of this distortion by optics or electrical method, can obtain the real-time information of biochemical reaction.Compare with traditional immuno-sensing method, the method need not to use any enzyme mark, fluorescent material and radioactivity as the reaction tracer agent, eliminated the impact of labeling process, highly sensitive (than the high several times of enzyme linked immune assay), can also come by monitoring little beam distortion the course of reaction of real-time, quantitative monitoring antigen-antibody, obtain the information of abundanter immune biochemical reaction.Through development these years, micro-cantilever sensing is used as a kind of emerging technology, compare research at the aspects such as bioengineering and environmental pollution monitoring technology and traditional method, such as the rna transcription factor, enzyme, mercury emissions and volatile compound etc., because the gauge of micro-cantilever only is sub-micrometer scale, to little beam surface biochemical reaction (such as, the probe molecule of modifying is combined with target molecule) STRESS VARIATION that causes sensitivity very, make its detection limit reach every milliliter of nanogram even Ya Nake level, be better than conventional enzyme-linked immunoassay method.
On single micro-cantilever detection system basis, for further eliminating the fast parallel detection of the ground unrest impacts such as the environment temperature is floated, solution variations in refractive index, the multiple target molecules of realization, the micro-cantilever sensing technology is just progressively to many arrays development.Reported that the method that realizes the micro-beam array sensing Study of An mainly contains: (1) utilizes vertical cavity surface emitting laser device that the sequential array light source is provided, micro-beam array is shone one by one, and recycling Optoelectronic Position Sensitive Detector (PSD) receives detection to the defection signal of each little beam; (2) utilize area source irradiation micro-beam array after expanding, record the deformation detection that image before and after the two-dimentional micro-beam array distortion carries out little beam with CCD.But because the neighbor distance of vertical cavity surface emitting laser device emission light beam can not be regulated, it can only shine for the certain micro-beam array of spacing, and dirigibility is lower and price is also very expensive; In the CCD area source detection method, because the bending at little beam tip can make image produce disperse, have a strong impact on the detection quality of spot displacement, cause its detection sensitivity not high, and speed is also slower during multi-channel detection.
How to utilize simple light path to design convenient and practical sensor-based system, realize the micro-beam array high sensitivity, fast, parallel deformation detection, develop micro-beam array immune sensing device, and utilize the array immunization sensor to carry out the antibody affinity costant and measure and be applied to how residual in the food security and the parallel real-time in-situ of contents of many kinds of heavy metal ion detects, be the focus of biochemistry detection field concern always.
Summary of the invention
Mentality of designing of the present utility model is: utilize acoustooptic deflector to order about the laser beam generation periodic deflection that laser instrument emits, with the scanning micro-beam array; By the optical lever principle each little deflection of beam deformation signal in the micro-beam array is amplified again, receive with Optoelectronic Position Sensitive Detector (PSD) sequential and detect, thus the biochemical reaction process information on each little beam of Real-Time Monitoring.
A kind of micro-cantilever array biochemical sensitive method based on acoustooptic modulation, step comprises:
Utilize first acoustooptic deflector to order about the laser beam that laser instrument emits and produce periodic deflection, scan micro-beam array with the laser beam of this periodic deflection;
By the optical lever principle each little deflection of beam deformation signal in the micro-beam array is amplified again;
Then use the Bending Deformation signal after Optoelectronic Position Sensitive Detector PSD sequential receives the described amplification of detection, thus the biochemical reaction process information on each little beam of Real-Time Monitoring.
Described acoustooptic deflector adopts acousto-optic modulator to get final product.
A kind of device that uses said method comprises laser instrument, acousto-optic modulator, biochemical reaction tank, micro-beam array, Optoelectronic Position Sensitive Detector PSD and monitoring means;
Described acousto-optic modulator is on the light path of the collimated laser beam that laser instrument sends;
Described micro-beam array is in biochemical reaction tank, and micro-beam array is on the light path of the emergent light of adjusting acousto-optic modulator; Described Optoelectronic Position Sensitive Detector PSD target surface is on the catoptrical light path of micro-beam array; The signal output part of described Optoelectronic Position Sensitive Detector PSD connects the signal input part of monitoring means;
Described acousto-optic modulator comprises acousto-optic medium and piezoelectric transducer; The ultrasound wave that produces same frequency behind the described piezoelectric transducer reception carrier frequency signal imports acousto-optic medium into; Described collimated laser beam obtains emergent light after producing refraction behind the acousto-optic medium.
The incident angle that described collimated laser beam is injected acousto-optic modulator meets the Bragg diffraction angle.Described carrier frequency signaling is ultrasound wave.
Also comprise reflective mirror, reflective mirror is on the light path between acousto-optic modulator and the micro-beam array; The emergent light of acousto-optic modulator is mapped on the micro-beam array after the reflective mirror reflection.
Described biochemical reaction tank is connected with heating arrangement, and heating arrangement is controlled by temperature controller.
In view of the sensitivity of micro-beam array biochemical sensitive Parallel detection and the laser beam that is radiated on the micro-beam array have than Important Relations, the utility model utilizes the Method And Principle collimation laser beam modulation of acoustooptic modulation, and comparing with existing micro-beam array biochemical sensitive parallel detecting method has the following advantages:
1) the detection light channel structure is simple, realizes easily;
2) scanning stepping amount can be regulated arbitrarily, can both conveniently position detection to the micro-beam array of various spacings, and dirigibility is stronger;
3) use same laser scans, guaranteed the consistance of radiation source on the little beam of each root of micro-beam array;
4) do not have mechanical rotation in the scanning process, precision is high;
5) use the integrated micro-beam array biochemical sensor volume of the method little, lightweight, conveniently moving.
Description of drawings
Fig. 1 is based on the micro-beam array biochemical sensitive device global design synoptic diagram of acoustooptic modulation; Among the figure:
Acousto-optic modulator 3, micro-beam array 4, Optoelectronic Position Sensitive Detector PSD5, A/D converter 6, temperature controller 7, computing machine 8, biochemical reaction tank 9, heating plate 10, reflective mirror 11, laser instrument 12;
Fig. 2 acousto-optic modulator principle schematic;
Fig. 3 acoustooptic modulation drive laser beam scanning micro-beam array schematic diagram;
Fig. 4 (a) and Fig. 4 (b) are 250 μ m, 2 scanning shift curve maps of locating in interval in the micro-beam array substrate, and wherein, Fig. 4 (a) is directions X, and Fig. 4 (b) is Y-direction.
Laser beam is periodically strafed two fixed points 9 hours of spacing 250 μ m in the micro-beam array substrate back and forth, and on directions X and Y-direction, all keeping parallelism is consistent in two scanning sites, larger skew do not occur, and the illustrative system scanning optical path is stable.
Fig. 5 is two spot scan signal schematic representations on little beam;
Adjusting laser beam scanning site, periodically switch back and forth at the tip of the two little beams in accurate location respectively, gathers two little beam displacement signals.
Fig. 6 is the displacement curve figure of two little beams under Temperature Excitation;
The temperature of micro-beam array is progressively risen to 29 ℃ from 23 ℃, heat up after 6 ℃, the displacement response signal of two little beams has differed about 20nm, and error 5.6% (phase residual quantity 20nm is divided by total deflection 360nm) is consistent under same temperature variation excitation substantially.Because the micro-cantilever sensing technology mainly is for intermolecular specific binding to the detection of biochemical reaction, as long as therefore can accurately measure this distinctive reaction information, the little beam deflection signal errors that receives on the PSD target surface is not affect testing result about 10%.
Fig. 7 utilizes micro-beam array to detect the specific binding of CLEN antigen-antibody;
After half an hour, add first the CAP standard specimen of 500ng/mL at mobile PBS, this moment, two beam response amounts were consistent, and amplitude is less, illustrates: (1) this response signal may be to be caused by environmental perturbation (temperature is floated, solution refractive index and potential of hydrogen variation etc.); (2) clenbuterol hydrochloride antibody and the CAP standard specimen modified on the beam 1 do not react.After signal is steady, the CLEN standard specimen that adds again 10ng/mL, beam 1 response signal that be modified with CLEN antibody this moment is obviously greater than beam 2 response signals of unmodified CLEN antibody, and illustrate: the specific reaction that the CLEN antigen-antibody has occured on (1) beam 1 has caused the variation of beam upper surface stress; (2) the response signal amplitude of beam 2 is less, may be to be caused by environmental perturbation.At last, beam 1 response signal is deducted beam 2 (with reference to beam) response signal, can obtain only by the true little beam deformation signal (45nm) of CLEN antigen and antibody specific in conjunction with generation.
Embodiment
A kind of micro-cantilever array biochemical sensitive method based on acoustooptic modulation, step comprises: utilize first acoustooptic deflector to order about the laser beam that laser instrument emits and produce periodic deflection, scan micro-beam array with the laser beam of this periodic deflection; By the optical lever principle each little deflection of beam deformation signal in the micro-beam array is amplified again; Then use the Bending Deformation signal after Optoelectronic Position Sensitive Detector PSD sequential receives the described amplification of detection, thus the biochemical reaction process information on each little beam of Real-Time Monitoring.Described acoustooptic deflector adopts acousto-optic modulator to get final product.
A kind of device that uses said method comprises laser instrument, acousto-optic modulator, biochemical reaction tank, micro-beam array, Optoelectronic Position Sensitive Detector PSD and monitoring means; Described acousto-optic modulator is on the light path of the collimated laser beam that laser instrument sends; Described micro-beam array is in biochemical reaction tank, and micro-beam array is on the light path of the emergent light of adjusting acousto-optic modulator; Described Optoelectronic Position Sensitive Detector PSD target surface is on the catoptrical light path of micro-beam array; The signal output part of described Optoelectronic Position Sensitive Detector PSD connects the signal input part of monitoring means; Described acousto-optic modulator comprises acousto-optic medium and piezoelectric transducer; The ultrasound wave that produces same frequency behind the described piezoelectric transducer reception carrier frequency signal imports acousto-optic medium into; Described collimated laser beam obtains emergent light after producing refraction behind the acousto-optic medium.
The incident angle that described collimated laser beam is injected acousto-optic modulator meets the Bragg diffraction angle.Described carrier frequency signaling is ultrasound wave.Also comprise reflective mirror, reflective mirror is on the light path between acousto-optic modulator and the micro-beam array; The emergent light of acousto-optic modulator is mapped on the micro-beam array after the reflective mirror reflection.Described biochemical reaction tank is connected with heating arrangement, and heating arrangement is controlled by temperature controller.
Specific in this example:
Acousto-optic modulator is made of as shown in Figure 2 acousto-optic medium and piezoelectric transducer, its principle is, when certain special carrier frequency signal driver transducer, transducer namely produces the ultrasound wave of same frequency and imports acousto-optic medium into, in medium, form variations in refractive index, the at this moment effect similar " phase grating " of medium, the light beam direction of propagation that changes light that interacts during by medium produces diffraction, when incident angle is the Bragg diffraction angle, outgoing beam only is it ± 1 order diffraction light, and exit direction deflection with the variation that loads frequency of carrier signal.
For realizing the high sensitivity to biochemical reaction information on the micro-beam array, quick, parallel detection, the utility model utilizes the acoustooptic modulation method to realize laser beam to the parallel detection of micro-beam array biochemical sensitive, and scheme is as follows:
Based on the micro-beam array biochemical sensitive device global design synoptic diagram of acoustooptic modulation as shown in Figure 1: the piezoelectric transducer end that frequency periodically variable ultrasonic signal between 70MHz and 90MHz is loaded on acousto-optic modulator, laser instrument (diameter 8mm, long 40mm, it is adjustable to converge the laser spots focal length) collimated laser beam (diameter 200 μ m, wavelength 650nm) that sends is with Bragg diffraction angle incident sound photomodulator (acousto-optic medium TeO
2), adjust the incident angle of laser beam, make the luminous power of the laser of from acousto-optic modulator, launching keep constant, outgoing beam this moment periodic scan in 3 ° of angular regions, adjust mirror position and laser beam is shone after reflection be fixed on micro-beam array gilding (environment temperature is controlled by heating plate by temperature controller in the pond) in the airtight biochemical reaction tank (volume 0.5ml), reflex to the vertical side-play amount of the little beam of each root on the reducible micro-beam array of spot displacement signal on the Optoelectronic Position Sensitive Detector (PSD) by collection, after the A/D conversion, input computing machine, realize the parallel detection of micro-beam array biochemical sensitive.
In embodiment:
One commercialization micro-beam array (wide 90 μ m, thick 1 μ m, the surface is coated with the thick gold layer of 0.02 μ m, adjacent little beam center distance is 250 μ m for German micromotive company, little beam length 500 μ m wherein) is positioned in the system shown in Figure 1;
As shown in Figure 1 with acousto-optic modulator (modulation wavelength 633～670nm, centre frequency 80MHz, modulation band-width 50MHz) and semiconductor laser be placed in the system, acousto-optic modulator load signal frequency periodically variable ultrasound wave between 70MHz to 90MHz, the position of adjusting the laser beam incident acousto-optic modulator makes the luminous power of the laser beam of launching after penetrating acousto-optic modulator keep stable;
With laser beam irradiation to the micro-beam array substrate, and two fixed points 9 hours of periodically strafing back and forth spacing 250 μ m, the scanning shift curve map as shown in Figure 4: on directions X and Y-direction, all keeping parallelism is consistent in two scanning sites, larger skew do not occur, the illustrative system scanning optical path is stable;
Adjusting laser beam scans the site, accurately locates the tip of two little beams, and periodicity is switched back and forth and gathered displacement signal, and synoptic diagram as shown in Figure 5; After little beam displacement signal is stable, with high-precisive temperature controllers (0.01 ℃ of precision) temperature of micro-beam array is progressively risen to 29 ℃ from 23 ℃, gained corresponding data curve is as shown in Figure 6.As can be seen from Figure 6 after 6 ℃ of intensifications, the displacement response signal of two little beams has differed about 20nm, and error 5.6% (phase residual quantity 20nm is divided by total deflection 360nm) is consistent under same temperature variation excitation substantially.Because the micro-cantilever sensing technology mainly is for intermolecular specific binding to the detection of biochemical reaction, as long as therefore can accurately measure this distinctive reaction information, the little beam deflection signal errors that receives on the PSD target surface is not affect testing result about 10%.
Experiment reagent:
Clenbuterol hydrochloride antibody, clenbuterol hydrochloride standard model CLEN, chloromycetin standard model CAP (above 3 kinds of samples are all taken from China Agricultural University's agronomy and biotechnology institute); Activator: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N-Hydroxysulfosuccinimide (NHS); Mercaptan HS-CH2-COOH (above 3 kinds of medicines are all purchased the company in SIGMA); PBS (4.0g NaCl+0.1gKH
2PO
4+ 1.48g Na
2HPO
4H
2The O+500ml deionized water); TPBS (PBS+0.5%Tween-20); 98% concentrated sulphuric acid; 30% hydrogen peroxide, it is pure to be analysis.
The modification of antibody on the micro-beam array:
Clean micro-beam array, the immersion ratio is 1: 3 H
2O
2And H
2SO
410min in the mixed solution (room temperature), take out and use deionized water rinsing, put into orifice plate, add the 0.1mol/L mercaptan of 200 μ L after sealing leave standstill 20h (room temperature), the sulfydryl that utilizes mercaptan to carry (HS) self-assembles on the gold-plated surface of micro-beam array one side.After reaction is finished, take out the micro-beam array alcohol flushing, use again deionized water rinsing, put into new orifice plate, inject the 0.2mol/L EDC of 100 μ L and the 0.05mol/L NHS of 100 μ L and leave standstill 1.5h, the carboxyl of mercaptan on the activation micro-beam array.Subsequently micro-beam array is taken out and use deionized water rinsing, be put into again the capillary array fit and modify on the platform, No. 1 little beam is carried out the clenbuterol hydrochloride antibody modification.Then take out micro-beam array and wash with TPBS, be fixed in the biochemical reaction tank again, the PBS damping fluid that flows has been debugged light path and has been tested.
The micro-beam array testing result:
Micro-beam array to the testing result of CLEN antigen and antibody specific reaction as shown in Figure 7, after adding first the CAP standard specimen of 500ng/mL among the figure, two beam response amounts are consistent, and amplitude is less, illustrates: (1) this response signal may be to be caused by environmental perturbation (temperature is floated, solution refractive index and potential of hydrogen variation etc.); (2) clenbuterol hydrochloride antibody and the CAP standard specimen modified on the beam 1 do not react.After signal is steady, the CLEN standard specimen that adds again 10ng/mL, beam 1 response signal that be modified with CLEN antibody this moment is obviously greater than beam 2 response signals of unmodified CLEN antibody, and illustrate: the specific reaction that the CLEN antigen-antibody has occured on (1) beam 1 has caused the variation of beam upper surface stress; (2) the response signal amplitude of beam 2 is less, may be to be caused by environmental perturbation.At last, beam 1 response signal is deducted beam 2 (with reference to beam) response signal, can obtain only by the true little beam deformation signal (45nm) of CLEN antigen and antibody specific in conjunction with generation.
Claims (3)
1. the micro-cantilever array biochemical sensitive device based on acoustooptic modulation is characterized in that comprising laser instrument, acousto-optic modulator, biochemical reaction tank, micro-beam array, Optoelectronic Position Sensitive Detector PSD and monitoring means;
Described acousto-optic modulator is on the light path of the collimated laser beam that laser instrument sends;
Described micro-beam array is in biochemical reaction tank, and micro-beam array is on the light path of the emergent light of adjusting acousto-optic modulator; Described Optoelectronic Position Sensitive Detector PSD target surface is on the catoptrical light path of micro-beam array; The signal output part of described Optoelectronic Position Sensitive Detector PSD connects the signal input part of monitoring means;
Described acousto-optic modulator comprises acousto-optic medium and piezoelectric transducer; The ultrasound wave that produces same frequency behind the described piezoelectric transducer reception carrier frequency signal imports acousto-optic medium into; Described collimated laser beam obtains emergent light after producing refraction behind the acousto-optic medium.
2. described device according to claim 1 is characterized in that described carrier frequency signaling is ultrasound wave.
3. described device according to claim 1 is characterized in that also comprising reflective mirror, and reflective mirror is on the light path between acousto-optic modulator and the micro-beam array; The emergent light of acousto-optic modulator is mapped on the micro-beam array after the reflective mirror reflection.
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Granted publication date: 20130220 Termination date: 20140427 |