CN1796989A - Method and devices of biochemical detection by using micro semi girder - Google Patents
Method and devices of biochemical detection by using micro semi girder Download PDFInfo
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- CN1796989A CN1796989A CN 200410103903 CN200410103903A CN1796989A CN 1796989 A CN1796989 A CN 1796989A CN 200410103903 CN200410103903 CN 200410103903 CN 200410103903 A CN200410103903 A CN 200410103903A CN 1796989 A CN1796989 A CN 1796989A
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Abstract
The invention is a biochemical detecting method and device using micro cantilever beam, using a micro cantilever made of silicon coated with biochemical sensitive layer as a biochemical molecule detecting element. As the measured matter enters into the bio-sensitive layer, the bio-sensitive layer absorbs the molecules of the measured matter to make the molecules of the measured matter and those of the bio-sensitive layer interact on each other by force so as to make the micro cantilever beam generate a surface stress whose change will bend the micro cantilever beam, a laser beam reflected from the back of the micro cantilever beam is received by a position sensitive detector, the deformation of the micro cantilever beam will make the laser spot shift on the position sensitive detector, the position sensitive detector converts the optical signal displacement into an electric signal, which is collected through a data collection card into a computer and expressed by image. The invention has high sensitivity and can serve as a biochemical sensor for detecting trace biochemical molecules.
Description
Technical field
The present invention relates to utilize micro-cantilever to carry out the method and the device of biochemistry detection.
Background technology
The ultimate principle of surveying the biology sensor of various biological and chemical material molecules is physics or the chemisorption of analyzed molecule on biochemical sensitive layer, is converted into electric signal by transducer.Existing biochemical sensor is designed to diaphragm type more, because conversion of signals device sensitivity restriction also is restricted the sensitivity of biology sensor.
Scanning probe microscopy SPM (Scanning Probe Microscope) is a kind of based on physics, and collection various modern technology is the novel surface analytical instrument of one.It is the main tool of nanotechnology research, is the highest microscope of resolution in the world.Atomic force microscope (AFM) is one of numerous members in the scanning probe microscopy SPM family, and it can observe the microscopic appearance of insulator surface near atomic scale.The principle of work of atomic force microscope (AFM) is: make the needle point convergence sample surfaces on the micro-cantilever and contact gently with the surface, owing to exist faint coulomb repulsion power and make micro-cantilever bending slightly between the most advanced and sophisticated atom of needle point and the sample surfaces atom.When needle point scans, can control piezoelectric ceramic scanatron by feedback system stretches and keeps interatomic acting force constant, the micro-cantilever that has needle point will tremble along with the fluctuating of sample surfaces, utilize beam of laser to shine the back side of micro-cantilever, micro-cantilever reflexes to laser beam on the position-sensitive detector, the laser intensity difference that the different quadrants of position-sensitive detector receive and the deformation quantity of micro-cantilever are the certain proportion relation, obtain the sample surfaces feature image thus.Because micro-cantilever is very responsive to the variation of power, thus atomic force microscope can high resolving power to the imaging of material surface pattern, the research surface nature.
Summary of the invention
The objective of the invention is to overcome the shortcoming of prior art, a kind of method and device that utilizes micro-cantilever to carry out biochemistry detection is provided, the present invention is highly sensitive, can be used as biochemical sensor and is used to detect micro-biochemical molecular.
The present invention takes following technical scheme:
The micro-cantilever that the present invention makes with the silicon of the special biochemical sensitive layer of coating is as the detecting element of biochemical molecular, and after measured matter entered the bio-sensing layer, the response frequency or the surface stress of micro-cantilever changed.When sensitive layer absorption measured matter molecule, make the interaction of surveying material molecule and sensitive layer molecule generation power to make micro-cantilever produce surface stress that the change of micro-cantilever surface stress will make the micro-cantilever bending.The slight curves of micro-cantilever detects with the light lever method.In optical lever method detection system, beam of laser is through the micro-cantilever backside reflection, the laser light reflected bundle is received by position sensitive detector (PSD), the deformation of micro-cantilever will make laser facula produce displacement on position-sensitive detector, position-sensitive detector is converted into electric signal with the light signal displacement, by data collecting card these signals is deposited in computing machine graphical representation.
The present invention includes laser tube, first catoptron, lens, micro-cantilever, mozzle, second catoptron, position-sensitive detector, sample cell, constant-temperature temperature-control device.
Described micro-cantilever is long 100～500 μ m, wide 10～100 μ m, the rectangle of thick 100～5000nm.
Described micro-cantilever is fixed on the supporting chip, and chip is long 3mm, wide 1.5mm, thick 0.3mm rectangle.
Described biochemical sensitive layer surrounds whole micro-cantilever.
Before first catoptron was fixed on laser tube, minute surface and laser incident ray were angled, to guarantee that laser can reflex on the lens through first catoptron.Lens are a right cylinder, cylindrical lower plane from midline position to form an angle upward to cutting out an inclined-plane with lower plane, back two/the part of micro-cantilever supporting chip is fixed on the inclined-plane center line, and the part of the first two branch of micro-cantilever and supporting chip is under the lens lower horizontal plane.Sample cell is equipped with radiator valve under the bottom surface, the temperature control when being used for guaranteeing to detect.The lens that micro-cantilever is housed place in the sample cell, the upper horizontal plane of lens contacts with air, lower horizontal plane contacts with sample liquids, and promptly the sample liquid level can not be higher than the upper horizontal plane of lens, and the effect of lens is to make the fluctuation of sample liquid level not influence the whole optical path of laser.Second catoptron and laser tube and first catoptron receive micro-cantilever laser light reflected bundle to guarantee second catoptron in same vertical plane and highly consistent, second catoptron laser-bounce on the sensitive detectors of position.
Laser tube sends beam of laser and passes lens through catoptron, under lens, micro-cantilever is housed, laser beam passes lens and penetrates on micro-cantilever, micro-cantilever incides lens to laser again, the laser that lens penetrate incides on the catoptron, and the laser that mirror reflects goes out is on the sensitive detectors of position.When radiator valve guarantees temperature constant, when measured matter flows to sample cell by mozzle, when the micro-cantilever of the biochemical sensitive layer of coating contacts with measured object, micro-cantilever produces surface stress and bends, make the laser facula of position-sensitive detector change, position-sensitive detector measures these variable quantities, collects these variable quantities by data collecting card again, the data of these variable quantities are deposited in computing machine, go out these variable quantities with graphical representation.
The present invention has following good effect:
1, with the detecting element of micro-cantilever as biochemical molecular, have very high sensitivity, the trace that can measure molecular level changes.
2, can carry out detection of dynamic, from a few minutes to continual continuous coverage in continuous tens hours.
3, has stable mechanical supporting mechanism.
4, added thermostatically-controlled equipment, when having guaranteed biochemical reaction to the requirement of temperature.
5, the deformation of optical lever method detection micro-cantilever has very high sensitivity, and vertical resolution can reach 0.1 dust, and is easy and simple to handle.
6, under the lens micro-cantilever is housed, can guarantees that the fluctuation of sharp sample liquid level does not influence the whole optical path of laser.
Description of drawings
Fig. 1 is the enlarged drawing of micro-cantilever 4, among the figure: 4 micro-cantilevers, 12 supporting chips.
Fig. 2 is a structural representation of the present invention; Among the figure: 1 laser tube, 2 first catoptrons, 3 lens, 4 micro-cantilevers, 5 mozzles, 6 sample cells, 7 second catoptrons, 8 position-sensitive detectors, 9 constant-temperature temperature-control devices.
Fig. 3 is made the sample test synoptic diagram by the inventive method and device.
Fig. 4 is the testing result curve map of the specific embodiment of the invention.
Embodiment
The present invention is further illustrated below in conjunction with the drawings and specific embodiments.
As shown in Figure 1, micro-cantilever 4 is a rectangle, is fixed on the supporting chip 12.
As shown in Figure 2, the present invention includes laser tube 1, first catoptron 2, lens 3, micro-cantilever 4, mozzle 5, second catoptron 7, position-sensitive detector 8, sample cell 6, constant-temperature temperature-control device 9.Before first catoptron 2 is fixed on laser tube 1, the minute surface of first catoptron 2 and laser incident ray are angled, to guarantee that laser can reflex on the lens 3 through first catoptron 7, lens 3 are a right cylinder, cylindrical lower plane from midline position to form an angle upward to cutting out an inclined-plane with lower plane, back two/the part of micro-cantilever 4 supporting chips is fixed on the inclined-plane center line, and the part of the first two branch of micro-cantilever 4 supporting chips is under lens 3 lower horizontal planes.Sample cell is equipped with thermostatically-controlled equipment 9 under 6 bottom surfaces, the temperature constant when being used for guaranteeing to detect.The lens 3 that micro-cantilever 4 is housed are placed on 6 li of sample cells, the upper horizontal plane of lens 3 contacts with air, lower horizontal plane contacts with sample liquids, and promptly the sample liquid level can not be higher than the upper horizontal plane of lens 3, and the effect of lens 3 is to make the fluctuation of sample liquid level not influence the whole optical path of laser.Second catoptron 7 and laser tube 1 and first catoptron 2 are in same vertical plane and highly consistent, guaranteeing that second catoptron 7 receives micro-cantilever 4 and reflects the laser that appears through lens 3, second catoptron 7 laser-bounce on position sensitive detectors 8.
When sending beam of laser, laser tube 1 passes lens 3 through catoptron 2,3 times micro-cantilever is housed at lens, laser beam passes lens 3 and penetrates on micro-cantilever 4, micro-cantilever 4 arrives lens 3 to laser-bounce again, the laser projections that lens 3 penetrate is to catoptron 7, and the laser that catoptron 7 reflects is on position sensitive detectors 8.Thermostatically-controlled equipment 9 guarantees temperature constant.When measured matter flows to sample cell 6 by mozzle 5, when the micro-cantilever 4 of the biochemical sensitive layer of coating contacts with measured object, the sensitive layer of micro-cantilever 4 adsorbs tested molecule, the interaction of tested molecule and sensitive layer molecule generation power, to make micro-cantilever produce surface stress, the change of micro-cantilever surface stress will make its bending, laser spot position changes, position-sensitive detector 8 measures these variable quantities, collect these variable quantities by data collecting card again, the data of these variable quantities are deposited in computing machine, go out these variable quantities with graphical representation.
Application the inventive method shown in Figure 3 and the device sample test of doing test.Micro-cantilever 4 usefulness silicon materials are made, metal-plated membrane on micro-cantilever 4, the about 20nm of thickness, the solution flushing micro-cantilever 4 of using 3: 7 proportioning ratio proportioning of sulfuric acid and hydrogen peroxide to go out repeatedly, micro-cantilever 4 is contained in lens places sample cell 63 times, laser tube 1 sends beam of laser shown in Fig. 3 solid arrow, pass lens 3 through catoptron 2,3 times micro-cantilever is housed at lens, laser beam passes lens 3 and penetrates on micro-cantilever 4, micro-cantilever 4 arrives lens 3 to laser-bounce again, and lens 3 emitting lasers incide on the catoptron 7, and the laser that catoptron 7 reflects is on position sensitive detectors 8.The PPS damping fluid that will contain single stranded DNA injects sample cell 6 from mozzle 5, when absorption takes place in the metallic atom that is plated on the micro-cantilever 4 when the single stranded DNA that is dissolved in the PPS damping fluid and being coated with, micro-cantilever bends owing to stress, laser spot position changes to some extent along with micro-cantilever bends on the position-sensitive detector 8, shown in dotted arrow among Fig. 3, position-sensitive detector 8 detects the displacement of hot spot, the data collecting card continuous acquisition is drawn test result such as Fig. 4 on computers to the displacement that changes, point 1 place is not for adding laser facula before the single stranded DNA in the position of position-sensitive detector 8, when the single stranded DNA that is dissolved in the PPS damping fluid joins in the sample cell 6, single stranded DNA and be coated with the gold atom generation suction-operated that is plated on the micro-cantilever 4, cause micro-cantilever since STRESS VARIATION bend through tens second laser facula move a little 2 places in the position of position-sensitive detector 8, and reach balance.Point 1 and the point 2 alternate position spike Δ Y in the Y direction are exactly the deformation of micro-cantilever, can calculate micro-cantilever 4 what single stranded DNAs of absorption according to Δ Y.
Can make people from solution, catch micro-biomolecule by the present invention, the sensitivity that improves biology sensor is had great significance.The present invention can be in each side widespread uses such as biological study, biomedicines.
Claims (3)
1, a kind of method of utilizing micro-cantilever to carry out biochemistry detection is characterized in that, the micro-cantilever made from the silicon materials of the biochemical sensitive layer of coating [4] is as the detecting element of biochemical molecular; After measured matter enters the bio-sensing layer, biochemical sensitive layer absorption measured matter molecule, the interaction of measured matter molecule and sensitive layer molecule generation power makes micro-cantilever [4] produce surface stress, and the change of micro-cantilever [4] surface stress will make micro-cantilever [4] bending; A branch of laser beam through micro-cantilever [4] backside reflection is received by position sensitive detector [8], the deformation of micro-cantilever [4] will make luminous point go up at position-sensitive detector [8] and produce displacement, position-sensitive detector [8] is converted into electric signal with the light signal displacement, by data collecting card signal is deposited in computing machine graphical representation.
2, application rights requires the 1 described device that utilizes micro-cantilever to carry out the biochemistry detection method, it is characterized in that, comprise laser tube [1], first catoptron [2], lens [3], micro-cantilever [4], mozzle [5], second catoptron [7], position-sensitive detector [8], sample cell [6], constant-temperature temperature-control device [9]; It is preceding that first catoptron [2] is fixed on laser tube [1], the minute surface and the laser incident ray of first catoptron [2] are angled, to guarantee that laser can reflex on the lens [3] through first catoptron [7], lens [3] are a right cylinder, cylindrical lower plane from midline position to form an angle upward to cutting out an inclined-plane with lower plane, back two/the part of micro-cantilever [4] is fixed on the inclined-plane center line, and the part of the first two branch of micro-cantilever [4] is under lens [3] lower horizontal plane; Sample cell [6] is equipped with thermostatically-controlled equipment [9] under the bottom surface; The lens [3] that micro-cantilever [4] are housed are placed on sample cell [6] lining, and the upper horizontal plane of lens [3] contacts with air, and lower horizontal plane contacts with sample liquids, and promptly the sample liquid level can not be higher than the upper horizontal plane of lens [3]; Second catoptron [7] and laser tube [1] and first catoptron [2] in same vertical plane and highly consistent, second catoptron [7] laser-bounce on position sensitive detectors [8].
According to the described device that utilizes micro-cantilever to carry out the biochemistry detection method of claim 2, it is characterized in that 3, micro-cantilever [4] is a rectangle, biochemical sensitive layer of coating is fixed on the supporting chip on it.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004101039039A CN100458431C (en) | 2004-12-30 | 2004-12-30 | Method and devices of biochemical detection by using micro semi girder |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004101039039A CN100458431C (en) | 2004-12-30 | 2004-12-30 | Method and devices of biochemical detection by using micro semi girder |
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| CN1796989A true CN1796989A (en) | 2006-07-05 |
| CN100458431C CN100458431C (en) | 2009-02-04 |
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Cited By (11)
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| CN101750481A (en) * | 2008-12-12 | 2010-06-23 | 清华大学 | Integrated grating micro-cantilever biochemical sensor and chip manufacturing method |
| CN102538981A (en) * | 2012-02-10 | 2012-07-04 | 敦南科技（无锡）有限公司 | Photoelectric detector |
| CN103822651A (en) * | 2014-03-03 | 2014-05-28 | 安徽理工大学 | Plane mirror reflection based micro-cantilever deflection detecting system of micro-cantilever array sensor and detecting method |
| CN104198338A (en) * | 2014-08-21 | 2014-12-10 | 刘建林 | Sensor for measuring physical properties of liquid and measurement method thereof |
| EP2955507A1 (en) | 2014-06-12 | 2015-12-16 | Danmarks Tekniske Universitet | A substrate, an apparatus and a method of determining the presence of a molecule |
| CN106092409A (en) * | 2016-06-13 | 2016-11-09 | 常州大学 | Utilize the method that optics quickly measures DNA molecular intermolecular forces |
| CN106092380A (en) * | 2016-06-13 | 2016-11-09 | 常州大学 | A kind of micro-simply supported beam device measuring genetic fragment active force |
| CN106443075A (en) * | 2016-12-09 | 2017-02-22 | 南京大学 | Temperature control system and temperature control sample stage for atomic force microscope |
| TWI642939B (en) * | 2017-09-13 | 2018-12-01 | 誠希科技有限公司 | Optical system for detecting cantilever deformation and applications thereof |
| CN109269978A (en) * | 2018-11-16 | 2019-01-25 | 西南科技大学 | Measure the measuring device and measuring method of adhesion strength between solid liquid interface under electric field |
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| JP2000097825A (en) * | 1998-09-24 | 2000-04-07 | Nikon Corp | Spring characteristic measurement method and its device |
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| ATE346297T1 (en) * | 2002-09-24 | 2006-12-15 | Intel Corp | DETECTION OF MOLECULAR BINDING BY MONITORING FEEDBACK-CONTROLLED CANOMY DEFLECTIONS |
| US6952952B2 (en) * | 2002-11-01 | 2005-10-11 | Molecular Imaging Corporation | Topography and recognition imaging atomic force microscope and method of operation |
| CN1240994C (en) * | 2003-04-10 | 2006-02-08 | 北京大学 | Microcantilever sensor and its making method |
| CN1232987C (en) * | 2003-04-28 | 2005-12-21 | 浙江大学 | Liquid phase atom mechanics microscope probe |
| CN2816805Y (en) * | 2004-12-30 | 2006-09-13 | 中国科学院电工研究所 | Biochemical sensor |
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| CN101750481A (en) * | 2008-12-12 | 2010-06-23 | 清华大学 | Integrated grating micro-cantilever biochemical sensor and chip manufacturing method |
| CN101750481B (en) * | 2008-12-12 | 2013-06-19 | 清华大学 | Integrated grating micro-cantilever biochemical sensor and chip manufacturing method |
| CN102538981A (en) * | 2012-02-10 | 2012-07-04 | 敦南科技（无锡）有限公司 | Photoelectric detector |
| CN102538981B (en) * | 2012-02-10 | 2013-11-13 | 敦南科技（无锡）有限公司 | Photoelectric detector |
| CN103822651A (en) * | 2014-03-03 | 2014-05-28 | 安徽理工大学 | Plane mirror reflection based micro-cantilever deflection detecting system of micro-cantilever array sensor and detecting method |
| EP2955507A1 (en) | 2014-06-12 | 2015-12-16 | Danmarks Tekniske Universitet | A substrate, an apparatus and a method of determining the presence of a molecule |
| CN104198338A (en) * | 2014-08-21 | 2014-12-10 | 刘建林 | Sensor for measuring physical properties of liquid and measurement method thereof |
| CN106092409A (en) * | 2016-06-13 | 2016-11-09 | 常州大学 | Utilize the method that optics quickly measures DNA molecular intermolecular forces |
| CN106092380A (en) * | 2016-06-13 | 2016-11-09 | 常州大学 | A kind of micro-simply supported beam device measuring genetic fragment active force |
| CN106443075A (en) * | 2016-12-09 | 2017-02-22 | 南京大学 | Temperature control system and temperature control sample stage for atomic force microscope |
| TWI642939B (en) * | 2017-09-13 | 2018-12-01 | 誠希科技有限公司 | Optical system for detecting cantilever deformation and applications thereof |
| CN109269978A (en) * | 2018-11-16 | 2019-01-25 | 西南科技大学 | Measure the measuring device and measuring method of adhesion strength between solid liquid interface under electric field |
| CN109269978B (en) * | 2018-11-16 | 2024-01-30 | 西南科技大学 | Measuring device and measuring method for measuring adhesion force between solid-liquid interfaces under electric field |
| CN109323986A (en) * | 2018-11-30 | 2019-02-12 | 中国地质大学（武汉） | The test device and method of adhesion strength between a kind of gas hydrate and mineral grain |
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