CN103558393B - For the pick-up unit of trace target substance in blood sample - Google Patents
For the pick-up unit of trace target substance in blood sample Download PDFInfo
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- CN103558393B CN103558393B CN201310507336.2A CN201310507336A CN103558393B CN 103558393 B CN103558393 B CN 103558393B CN 201310507336 A CN201310507336 A CN 201310507336A CN 103558393 B CN103558393 B CN 103558393B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
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- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/5302—Apparatus specially adapted for immunological test procedures
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Abstract
The invention discloses a kind of pick-up unit for trace target substance in blood sample, comprising: detect raceway groove, one section, its downstream channel feature is the detection zone leaving detection window; Application of sample raceway groove, is connected to and detects raceway groove Upstream section and form application of sample bypass; Assist gallery, is connected on the detection raceway groove between application of sample raceway groove tie point and detection zone, forms the bypass of application of sample earial drainage; Signal piping unit, is coupled to detection raceway groove, and is provided with operation valve; Application of sample pipe-line cell group, is coupled to application of sample raceway groove and assist gallery, and is provided with operation valve group; Testing pump, detects raceway groove upstream extremity by signal piping unit and corresponding operation valve access; Sample-adding pump group, by application of sample pipe-line cell group and corresponding operation valve group access application of sample raceway groove; And control module, connect testing pump, sample-adding pump and operation valve and operation valve group, with logic control testing pump, sample-adding pump group and the operation valve that matches, operation valve group sequence of movement.Sampling and analyzing device is the sampling and analyzing device of optics.
Description
Technical field
The present invention relates to a kind of pick-up unit for trace target substance in blood sample, belong to field of biomedicine technology.
Background technology
The generation of human body diseases often produces the kind of biomolecule or the change of quantity in vivo, and people can be carried out the early diagnosis of disease by the change of the generation of some significant biomolecule in detection bodies or quantity or be understood the differentiation of disease.Such as, myoglobins Myoglobin during heart injury in blood, Mb, creatine kinase isozyme (Creatine Kinase MB, CK-MB) and cardiac muscle troponin I (Cardiac Troponin I, cTnI) protein molecular will produce, and concentration increases.Clinician comes Diagnosing Cardiac degree of injury or result for the treatment of by the content of these biochemical markers in body.But the specificity marker molecule content of most ailments is all very low, trace even ultratrace level detects these significant target materials and remains a huge challenge.
About trace, chemically refer to minimum amount, few only a little vestige.Trace analysis trace analysis, then refer to content in material 1,000,000/analytical approach of following combination.The implication of trace one word changes to some extent along with the development of Analytical Methods of Trace.Therefore, trace is the value of confining spectrum gradual change.
Trace analysis comprises and measures trace element total concentration in the sample and measure trace element in the sample or the distribution situation of specimen surface by probe technique.Generally be divided into 3 basic steps: sampling, sample pretreatment and mensuration, lay particular emphasis on mensuration link herein, but understand for contributing to, the first two link is only made a brief description.
Due to tested element, content is very low in the sample to which, distribution is very uneven, particularly environmental sample, and often in time, spatial variations fluctuation is very large, give one's full attention to samples' representativeness and ensure certain sample size.In order to strengthen the interference basic with removing of the Detection capability of trace constituent, the separation and consentration of trace components is usually absolutely necessary, and has two schemes: one is separated from sample key component, allows trace components stay in the solution; Another kind is separated by trace components and allows key component stay in the solution.In order to improve separation, concentration effect, usually apply macking technique.Another object of sample pretreatment trace components is changed into be most appropriate to the last form measured.Conventional separation, enrichment method have volatilization, precipitation and co-precipitation, electrolysis, liquid-liquid extraction, ion-exchange, chromatogram, extraction-chromatography, electrophoresis etc.To be given one's full attention to for the loss of pollution and trace components in separation, enrichment process.
Measure the method for trace components, depend on the sensitivity of analyzed object and assay method, accuracy, precision and selectivity and rationality economically.In the trace analysis methods such as from the colourimetry of classics and spectrophotometric method to the instrumental analysis in various modern age, comparatively conventional method has: 1. optical means.Comprise spectrophotometric method, atomic emission spectrometry, atomic absorption spectrophotometry, atomic fluorescence spectrometry, molecular fluorescence and phosphorimetry, chemoluminescence method, Laser Enhance Ionization Spectrometry etc.2. electrochemical method.Comprise polarogarphy, coulometry, potential method and chronoptentiometry etc.3. x-ray method.Comprise electron microprobe method, x ray fluorescence spectrometry etc.4. radiochemical method.Comprise activation analysis, isotope dilution method, radio-labeled assays's method etc.5. mass spectroscopy.Comprise SIMS analysis, spark source solid mass spectrum.6. chromatography.Comprise vapor-phase chromatography, liquid phase chromatography, the chromatography of ions etc.
Blood Biochemical mark common detection methods has radioimmunoassays RIAs, high pressure liquid chromatographic analysis method, electrochemical methods, protein analyzer, various diagnostic kit and immunity-chromatography test strip etc. clinically at present, these method ubiquity radioactive contamination, need large-scale instrument, length consuming time, the shortcoming such as quantitatively can not to detect, application clinically has certain limitation.Summary of the invention
The object of the invention is for overcoming above-mentioned the deficiencies in the prior art, providing a kind of structure letter to answer, the pick-up unit for trace target substance in blood sample that compact, detection efficiency is high.
For achieving the above object, the present invention adopts following technical proposals:
For a pick-up unit for trace target substance in blood sample, comprise sample adding device and to sample adding device obtain the sampling and analyzing device that sample detects, wherein said sample adding device comprises:
Detect raceway groove, one section of channel feature in its downstream is detection zone, and at least leaves detection window at detection zone place;
Application of sample raceway groove, is connected to the Upstream section of detection raceway groove and forms application of sample bypass;
Assist gallery, is connected on the detection raceway groove between application of sample raceway groove tie point and detection zone, is configured for the bypass of application of sample earial drainage; And the detection channel length between application of sample raceway groove and assist gallery is greater than the length of detection zone;
Signal piping unit, is coupled to detection raceway groove, and is provided with operation valve;
Application of sample pipe-line cell group, is coupled to application of sample raceway groove and assist gallery, and is provided with operation valve group;
Testing pump, is detected the upstream extremity of raceway groove, detects auxiliary liquid with pumping by described signal piping unit and corresponding operation valve access;
Sample-adding pump group, by described application of sample pipe-line cell group and corresponding operation valve group access application of sample raceway groove, with corresponding pumping sample adding liquid group; And
Control module, connects testing pump, sample-adding pump and operation valve and operation valve group, with the sequence of movement of logic control testing pump, sample-adding pump group and the operation valve that matches, operation valve group;
Described acquisition and analysis device is furnished with the driving mechanism driving it to move to each detection position, detection zone in turn;
Described sampling and analyzing device is the sampling and analyzing device of optics, mated, it comprises one and covers plate with detection window, detection window is wherein similar to the shape of detection zone on optical projection face, and on this optical projection direction, the area of detection window is 1.1 ~ 1.5 times of detection zone area.
Described driving mechanism is ball-screw screw mechanism.
Described detection raceway groove, application of sample raceway groove are identical with the runoff xsect of assist gallery, and are plane towards the face of checkout equipment.
Described application of sample raceway groove and assist gallery all with detection channel vertical.
Described detection raceway groove, application of sample raceway groove and assist gallery correspondence comprises the channel groove being formed in upper surface of substrate and the upper cover plate being covered in corresponding raceway groove upper surface, and wherein the runoff xsect of channel groove is semicircle or lower surface drift angle arcing square.
The width of rebate of described channel groove is 100 μm ~ 1000 μm.
One detects raceway groove, an application of sample raceway groove and an assist gallery forms an application of sample unit, and the detection raceway groove of multiple application of sample unit is connected in series or and connects.
And all detection raceway grooves connect are common junction circular array centered by inlet and with inlet.
Described detection zone length is 1.5 ~ 3 times of the detection channel length between application of sample raceway groove and assist gallery.
The invention has the beneficial effects as follows, according to the present invention, by means of simply constructed raceway groove, then the analysis of sample is coordinated, use Whole Equipment compact, application of sample amount is accurate and whole operation is relatively terse, and what institute's elapsed time was more is embodied on the reaction time, operational phase holding time is few, and overall detection efficiency is higher.Such as use sample adding device continuous sample-adding 10 times, the single sampling time was less than for 2 seconds, and measure application of sample amount volume each time, the coefficient of variation is less than 1%.
Accompanying drawing explanation
Fig. 1 a is an embodiment channel feature structural representation, and view before being expressed as application of sample;
Fig. 1 b is along a-a ' raceway groove filling damping fluid view;
Fig. 1 c is for pass into sample to be tested view along b-c-d-b ' raceway groove;
Fig. 1 d, for pass into damping fluid view along a-a ' raceway groove, pushes over cd section sample to be tested at the position covering detection zone e;
Fig. 2 a is the structural representation of sandwich structure in an embodiment;
Fig. 2 b is the structural representation of sandwich structure in another embodiment;
Fig. 3 is that a kind of nano-probe storage unit forms flow process;
Fig. 4 be carry out for luminescence probe usual sandwich structure, modify high loose nanometer thin rete at detection zone e and modify the comparison basis of high loose nanometer thin rete using further nano-probe storage unit three kinds of situation sensitizing effect at detection zone e;
Fig. 5 is the quantitative Detection results figure of the trace target substance that the sample of different target material concentration is realized by the detection of embodiment of the present invention method;
Fig. 6 is three kinds of biochip test Comparative result figure in embodiment;
Fig. 7 is the channel feature schematic diagram of parallel detection in an embodiment;
Fig. 8 is channel feature schematic diagram in another embodiment;
Fig. 9 is channel feature schematic diagram in another embodiment;
Figure 10 is a kind of channel feature structural representation;
Figure 11 is another kind of channel feature structural representation;
Figure 12 is optical detecting module structural representation;
Figure 13 is the principle of work schematic diagram that light path covers plate;
In figure: 1. detect raceway groove, 2. application of sample raceway groove, 3. detection zone, 4. substrate, 5. assist gallery, 6. seizure antibody, 7. target substance, 8. signal antibody, 9. probe molecule, 10. catch aptamer, 11. signal aptamers, 12. upper cover plates, 13. first type raceway grooves, 14. Second-Type raceway grooves, 15. cover plate, 16. lens, 17. 2 to spectroscope, 18. pin holes, 19. first optical filters, 20. photoelectric commutators, 21. data processing modules, 22. displays, 23. light sources, 24. second optical filters, 25. ball screw assembly,s, 26. effective fluorescence, 27. exciting lights, 28. invalid fluorescents, 29. biochips.
Embodiment
In order to make the object of embodiments of the invention, technical scheme and advantage clearly understand, below in conjunction with embodiment and accompanying drawing, the technical matters of many levels of the present invention and technological means used are described in detail.At this, illustrative examples of the present invention and illustrating only for explaining the present invention, but not as to concrete restriction of the present invention.
In such a concept, as detected raceway groove 1, it is a fluid passage in essence, and not for detection or raceway groove specifically limit.As the fluid passage of runoff, can use upstream, midstream and downstream to distinguish positions different on fluid circulating direction, those skilled in the art should be expressly understood this.
Be to be understood that, core word as detection window is " window ", but be not expressed as the window offered, and be expressed as can be used in detect, be one with " can " term that is limited, look far into the distance in fixed position as use telescope, around it, also meet the condition that can look far into the distance, but do not represent and establish window separately in position of telescope.
Should be appreciated that herein, as application of sample pipe-line cell, be not a pipeline, and should be understood to application of sample pipe system.
A pick-up unit measured for trace target substance 7, is configured to a biochip 29, sample adding device and a detection module for Detection of Weak Signals.
About biochip 29, also known as DNA chip or genetic chip, they are crystallizations that DNA hybridization probe technique combines with semi-conductor industry technology.This technology means and is fixed on after on holder by a large amount of probe molecule 9 and is with fluorescently-labeled DNA sample molecule to hybridize, by detecting the hybridization signal intensities of each probe molecule 9 and then obtaining quantity and the sequence information of sample molecule.In this article, substrate 4 and raceway groove add that biomolecule is configured to a biochip 29.
Biochip technology originates from making nucleic acid molecular hybridization.So-called biochip refers generally to the microarray hybridization cake core (micro-arrays) that high density is fixed on the biological information molecule (as genetic fragment, DNA fragmentation or polypeptide, protein, glycan molecule, tissue etc.) on mutual supporting dielectric, in array, the sequence of each molecule and position are known, and are pre-set sequence dot matrix.Micro-fluidic chip (microfluidic chips) and liquid phase biochip are the biochip new technologies than developing after micro-array chip, and biochip technology is the substance of Systems biotechnology.
Say more intuitively, biochip 29 puts biological sample exactly on the materials such as a piece of glass sheet, silicon chip or nylon membrane, then collects signal by a kind of instrument, uses Computer Analysis data result.
Although people may be easy to a biochip and electronic chip connects, and in fact, both truly have a common ground the most basic: the data message in microsize with magnanimity.But they are diverse two kinds of things, on electronic chip, Boulez is semi-conductor electricity subelement one by one, and on biochip Boulez be bioprobe molecule 9 one by one.
Therefore, as Figure of description 1a in the structure that makes, detection zone 3, the region that namely in figure, e represents, for fixed trapped material molecule, for catching the biomolecule in application of sample liquid.
For the measurement of trace target substance 7, in such a sample adding device, its basic configuration should comprise:
Detecting raceway groove 1, in the structure of figure as shown in 1a, is a straight raceway groove, and two ends are identified by a-a ', and a end is fluid upstream end, and the other end is then fluid outflow end.Be detection zone 3 at one section of channel feature in its downstream, and at least leave detection window at detection zone 3 place.
Ying Zhi, when detecting raceway groove 1 and bending or when there is bending structure, little on the fluid pumping impact of entirety, the detection raceway groove 1 be not specifically limited on this basis can be understood as and meets trend arbitrarily.
From flow resistance angle, preferably adopt straight channel structure, flow resistance is little, for identical pump, nominally can have larger lift.
Detect raceway groove 1 to get on to understand it from another one concept, predetermined substance can be transported to detection zone by the use detecting raceway groove.
So specific material is just carried by application of sample raceway groove 2, and it is connected to the Upstream section of detection raceway groove 1 and forms application of sample bypass, and the various fluids of application of sample are all carried by application of sample raceway groove 2.
Be to be understood that, because said various Fluid Volume is very little, so relevant channels cross-section is also not too large, according to not infiltrating and infiltration phenomenon of producing because of surface tension when solid and liquid comes into contact, thus can ensure that the application of sample liquid passage smaller in cross section is carried reliably by entirety.
Ying Zhi, does not infiltrate when showing as solid and liquid comes into contact, and surface of contact is tending towards reducing, liquid can not be attached to phenomenon on solid.As mercury can not be attached on glass, mercury is poured in glass container, the angle of mercury and glass wall contact position is greater than 90 °, shows that surface of contact is tending towards reducing, i.e. mercury not Sized glass.Water can not be attached on paraffin, illustrates that water does not infiltrate paraffin.
Concept on the other side is then infiltrate, and as being placed on a water on clean glass plate, can adhering to and form thin layer on a glass.One block of clean glass sheet is entered in water and takes out, glass surface can be stained with one deck water.This phenomenon is called infiltration.Concerning glass, water infiltrates liquid.
So associated as capillarity, infiltrate liquid and rise in kapillary (as water-glass), liquid level becomes concave moon surface type, and liquid is attached to wall; Do not infiltrate liquid to decline in kapillary (as mercury-glass), liquid level becomes gibbous moon face type, and liquid is non-cohesive at wall, and surface tension makes it protrude.
According to above-mentioned principle, overall conveyance can be carried out in the raceway groove that cross section is smaller to one section of liquid.
For sample adding device, in order to ensure normally carrying out of application of sample, configuration assist gallery 5 further, as shown in Figure 1a, assist gallery 5 forms another fluid passage with application of sample raceway groove 2 reality, is linked by the cd section sense channel shown in Fig. 1, forms b-c-d-b ' passage.Need auxiliary ditch to be configured to be connected on the detection raceway groove 1 between application of sample raceway groove 2 tie point and detection zone 3 to 5 like this, be configured for the bypass of application of sample earial drainage; And detection raceway groove 1 length between application of sample raceway groove 2 and assist gallery 5 is greater than the length of detection zone 3.
The requirement of length is inevitable diffusion phenomena between different liquid level, and cross section may be caused fuzzy, simultaneously about the amount of pumping liquid, and control that can not be desirable.In order to can given reaction be carried out in detection zone 3, need the liquid segment of application of sample can cover detection zone 3 completely, go forward side by side and may eliminate the impact of control accuracy and different liquids diffusion.
In order to obtain liquid cross-sectional relatively clearly, in the structure shown in Fig. 1 a, application of sample raceway groove 2 and assist gallery 5 are all vertical with detection raceway groove 1.
Arrange according to the simple above-mentioned raceway groove introduced, be the feeding meeting liquid so as to the channel system set up, need further its pipe arrangement.Due to as shown in Figure 1a, 4 interfaces altogether, and control mode is also uncomplicated, need not carry out complicated PIPING DESIGN, and only need also to distinguish according to required control mode fluidly to carry out pipe arrangement as " pipe arrangement databook ".
Pipe arrangement being divided into two large parts, being respectively detection raceway groove 1 unit for detecting raceway groove pipe arrangement and the application of sample pipe-line cell group for application of sample raceway groove 2 and assist gallery 5 pipe arrangement.Then configure relevant operation valve, control for the break-make detecting raceway groove 1, application of sample raceway groove 2 and assist gallery 5, wherein two raceway grooves are below because unitary construction is a fluid passage, should carry out synchro control.
In following content visible it, a end detecting raceway groove 1 is mainly used in pumping into a kind of liquid, and application of sample raceway groove 2 then needs to add two kinds of liquid.For this reason, the b end of application of sample raceway groove 2 can configure solenoid directional control valve, as three-position three-way valve, for the intervention of two kinds of liquid at Different periods, and closes down control.Also a threeway can be utilized to connect two pipelines, each pipeline configures an operation valve.
Simple with regard to pipe arrangement, generally also comprise the configuration of valve, therefore, for simple control, those skilled in the art can configure accordingly, and the pipeline flowing addressed due to the application is relatively simple, and its piping method does not repeat them here.
And then the configuration of pump is related to about described sample adding device, be also configured to testing pump and sample-adding pump group according to above-mentioned pipe arrangement, wherein the latter is preferably made into multiple according to the kind of liquid.
Testing pump detects the upstream extremity of raceway groove 1 by described signal piping unit and corresponding operation valve access, detects auxiliary liquid with pumping.
Sample-adding pump group then accesses application of sample raceway groove 2, with corresponding pumping sample adding liquid group by described application of sample pipe-line cell group and corresponding operation valve group.
And then in order to control better, configuration control module, connects testing pump, sample-adding pump and operation valve and operation valve group, with the sequence of movement of logic control testing pump, sample-adding pump group and the operation valve that matches, operation valve group.
Known according to aforesaid content, steering logic is relatively simple, the control algolithm that those skilled in the art can realize being correlated with without the need to paying creative work.
About raceway groove, from structure, the selection more excellent similarly herein is more open channel, its foundation structure with reference to open channel structure, can show as and detect raceway groove 1, application of sample raceway groove 2 is identical with the runoff xsect of assist gallery 5, and be plane towards the face of checkout equipment, be to be understood that accordingly, here plane is mainly conducive to effectively carrying out of detection, and the structure that xsect is identical, be then conducive to forming stable liquid section.
In certain embodiments, possible piecewise configures different structures, if part channel feature is pipe, and flows through district in liquid section tectonic province and liquid section and is configured to open channel structure.
Embody to some extent about the content more than content of liquid section, and have concrete application in content below, do not repeat them here.
In such as Figure 10 and structure as shown in figure 11, detect raceway groove 1, application of sample raceway groove 2 and assist gallery 5 correspondence and comprise the channel groove being formed in substrate 4 upper surface and the upper cover plate 12 being covered in corresponding raceway groove upper surface, wherein the runoff xsect of channel groove is semicircle or lower surface drift angle arcing square, wherein semicircle channel groove is expressed as the first type channel groove 13, and another kind of channel groove is then expressed as Second-Type channel groove 14.
Channel groove is molded over the upper surface of transparent substrate 4, if adopt Non-follow control, can be checked the flowing of fluid, can facilitate Non-follow control by the different colours of liquid.
About upper cover plate 12, because required substrate 4 upper surface area is also little, upper cover plate 12 can be one-piece construction, covers the upper surface of whole substrate 4.The upper cover plate 12 that also can carry out mating according to channel groove tendency is arranged.
About the specification of channel groove, limit according to its width of rebate, the width of rebate of described channel groove is 100 μm ~ 1000 μm.Concrete specification should adapt with the sensitivity of detecting instrument, and detecting instrument sensitivity is enough high, and micro-channel width can reduce.Concrete specification also has relation with promotion liquid by the pump of micro-raceway groove in addition, and micro-channel width dimension is less, and resistance is larger, and the expulsive force of the pump of needs is also larger.Therefore, the specification of channel groove should consider the driving force of pump and the sensitivity of detecting instrument, and the width of rebate of channel groove should not be less than 100 μm.
Again because raceway groove is unsuitable excessive, the amount coming from various liquid is also little, and too large cross section also can affect the quality that liquid section obtains simultaneously, and for this reason, the width of rebate of channel groove should not be greater than 1000 μm.
In the application of reality, we can face such problem, sometimes need to analyze multiple blood, or multiple samples of same blood sample are analyzed, in order to further improve detection efficiency, one detects raceway groove 1, application of sample raceway groove 2 and an assist gallery 5 forms an application of sample unit, the detection raceway groove serial connection of multiple application of sample unit or and connect, can carry out accordingly as detected while multiple blood sample.
As shown in Figure 7, there is multiple detection zone e in the longer detection raceway groove of aa ' of indicating, and then multiple application of sample raceway groove and assist gallery can be configured, like this, as a total detection raceway groove can once cover three detection zones, can save the consumption of sample on the whole, and minimizing consumes to the effect of auxiliary liquid, reduces follow-up processing load.On the other hand, the pipeline quantity of pipe arrangement can also be reduced, simplify overall structure.
Structure is as shown in Figure 7 a kind of version of serial, and structure is as shown in FIG. 8 and 9 parallel version, structure wherein shown in Fig. 8 is a kind of simple overlaying structure, is reducing to some extent perpendicular to one-piece construction on the direction of a-a', decreasing the application of base material.
Fig. 9 then indicates another kind of parallel organization, and all detection raceway grooves connect for common junction circular array, exist public node, can reduce pipeline and connect quantity centered by inlet.And if adopt same pump, the problem of different process in the parallel pipeline that the difference that can reduce intermediate duct length causes.
About the relations problems of detection raceway groove 1 length between application of sample raceway groove 2 and assist gallery 5 and detection zone 3 length, involved by having in aforesaid content, find through long-term experiment, when detection zone 3 length be detection raceway groove 1 length between application of sample raceway groove 2 and assist gallery 5 be not less than 1.5 times time, substantially there will not be the fuzzy and control accuracy of liquid surface to produce can not effectively produce interface clearly liquid section just cover the problem of detection zone completely, to ensure that target substance to be measured is trapped in detection zone 3 completely, guarantee Detection job.Nature, this needs the control accuracy of pump valve to coordinate with it, but pump valve type selecting does not belong to the content that this case needs are considered, under the pump valve configuration condition of degree of precision, above-mentioned multiple proportions is applicable.
But detection zone 3 is unsuitable long, so can produce excessive structure and the loss of reagent, for this reason, getting detection zone 3 length for detecting raceway groove 1 length 3 times is the upper limit.
Sample adding device is main improvement, and as pick-up unit, under the condition covering sample adding device, the checkout equipment that configuration is relevant, checkout equipment can adopt the checkout equipment of the known final thing in matching detection district.
Mated, one detects raceway groove 1, application of sample raceway groove 2 and an assist gallery 5 forms an application of sample unit, the detection raceway groove serial connection of multiple application of sample unit or and connect;
Correspondingly, described acquisition and analysis device be furnished with drive its move to the driving mechanism that position is detected in each detection zone 3 in turn.
In content as previously shown, the area of substrate is very little, correspondingly, distance between each detection zone also can be very little, and so driving mechanism must have enough driving precision, preferably, described driving mechanism is ball-screw screw mechanism, has reached required control.
In addition reference, if array chip micro-raceway groove location when fluoroscopic examination is the key factor affecting testing result, adopt the secondary key feature as location of precision lead screw, only have the positioning error of several microns in the displacement that precise ball screw pair 25 can reach 0.5 meter, the accurate positioning requirements of multiple micro-raceway groove detection zone on biochip can be met.
As shown in figure 12, in certain embodiments, a kind of acquisition and analysis device comprises:
Monochromatic source, according to given light path outgoing, the light source that light source 23, second optical filter 24 is as shown in Figure 12 formed, wherein light source 23 directly can adopt laser diode, and other laser pump (ing) also can be adopted to produce laser, and monochromaticity is relatively good.Also the laser of Single wavelength can be produced based on described second optical filter 24.
And then configuration shaping mirror group, being configured in the light path of monochromatic source, is given light beam by beam shaping; Be commonly called beam shaping mirror or beam shaping after shaping mirror group is packed, mainly for generation of suitable light beam, especially the good light beam of linearity, can ensure the controllability of light path, can obtain suitable light intensity again.
Further, plate 15 is covered in configuration, has via hole, is irradiated to selected detection zone 3 for described given light beam passes through, and passing through for detection zone 3 folded light beam; In structure as shown in fig. 13 that, detection zone 3 to be measured is made to be exposed to exciting light 27 times by covering plate 15, and other and its parallel detection district can not be excited by covering, even if or excited its fluorescence to pass on a small quantity, thus the problem that when effectively solving the parallel detection of many raceway grooves, fluorescence disturbs mutually.The reflected light in the namely target detection district 3 between clearly can taking a fancy in figure from outgoing the wish perforate covering plate 15, form effective fluorescence 26, and the reflected light of other two detection zones can be invalid fluorescence 28, can not be caught by corresponding optical device.
And then configuration pre-service optical element, be configured in folded light beam light path, for the pre-service of folded light beam, pre-service is limited to follow-up optical converter 20, is mated, both collaborative type selectings.
Mated, a photoelectric commutator 20, receive through pretreated described folded light beam, convert light signal to electric signal.
Data processing module 21, input connects described photoelectric commutator 20, calculates according to predetermined algorithm the electric signal obtained; And
Display 22, connects described data processing module 21, for output display result of calculation.
So, according to said structure, first light source sends exciting light, exciting light after filtration after mating plate purifying by two to dichroic mirror, through lens focus to micro-raceway groove detection zone e, excite stay detection zone e signal antibody 8 or signal aptamer 11 on fluorescent molecular probe, it is made to send fluorescence signal, this fluorescence signal to be covered after plate, lens through two to dichronic mirror through light path, the device that is photoelectrically converted after pin hole and optical filter purifying changes into electric signal, again through data processing, will be presented on liquid crystal display with target amount of substance to be measured.
About two to spectroscope 17, concrete configuration is that folded light beam is vertical with the light path of monochromatic source outgoing, and then described acquisition and analysis device also comprises the light path junction being configured in folded light beam and monochromatic source outgoing and is furnished with two to spectroscope 17, the plain coil of monochromatic source outgoing is reflected, and to folded light beam total transmissivity;
Correspondingly, two to spectroscope 17 between described pre-service optical element and described shaping mirror group.
Between spectroscope 17, a punctured element is also furnished with at pre-service optical element and two, pin hole 18 as shown in figure 12, for through giving the light beam of uniform section, and pre-service optical element is the first optical filter 19, to obtain the light beam that matching optics converter 20 gathers required wave band.
And the detection method on basis, we are defined as a biochip substrate 4 and the raceway groove be molded in substrate 4, like this, substrate 4 respectively end respectively coupling be provided with the inlet that communicate corresponding to each raceway groove and waste liquid outlet.As shown in Figure 1a.By controlling micro-raceway groove liquid flow, can realize on biochip the accurate application of sample of liquid.
Micro-raceway groove is provided with detection zone e, detection zone e internal fixtion has the seizure antibody 6 of target material to be measured or catches aptamer 10, the sandwich structure to target material to be measured can be formed in detection zone according to load procedure, utilize probe molecule 9 and nanometer sensitization to convert trace target substance signal to optics or electrical signal in detection zone.
Specifically comprise the following steps:
1) get a sample adding device, and be fixed for the biochip of catching marker substances to be detected in detection zone 3.
2) and then close application of sample raceway groove 2 and assist gallery 5, pump into damping fluid to detection raceway groove 1, at least fill the detection raceway groove 1 between application of sample raceway groove 2 and assist gallery 5; As shown in Figure 1, whether general have damping fluid to flow out the filling state judging damping fluid from liquid outlet by observing, this situation needs to fill it up with whole detection raceway groove, certainly, flow control can be passed through, the capacity matching carrying out flow and raceway groove controls, and under such controlled condition, related liquid need not be full of whole raceway groove.
3) detection raceway groove 1 is closed, pump into containing sample to be tested by application of sample raceway groove 2, assist gallery 5 earial drainage, sample to be tested at least fills the detection raceway groove 1 between application of sample raceway groove 2 and assist gallery 5, sample to be tested in this section forms detection segment, and wherein sample to be tested is the sample detecting marker substances containing described band; As illustrated in figure 1 c, the damping fluid of cd section is released by sample to be tested, and sample to be tested is trapped in bcdb ' pipeline, and wherein cd section row becomes required liquid section.
The keying that should be appreciated that about raceway groove is described in and only closedown is described herein, and clearly can know those raceway grooves by context and open.
4) and then, as shown in Figure 1, close application of sample raceway groove 2 and assist gallery 5, pump into damping fluid to detection raceway groove 1, detection segment is pushed to detection zone 3, and covers detection zone 3; Profile lines different in figure illustrates different liquid, has and clearly show in figure.
5) the first association reaction, the sample to be tested in detection segment and biochip reaction first given time, about the reaction time between related liquid, known by those skilled in the art, to this, repeats no more.
6) after the first association reaction, use damping fluid that described detection segment is released detection zone, then close and detect raceway groove.
7) mode utilizing step 3 identical with 4, uses semiochemicals liquid substitute sample to be tested and produce signal segment, covers detection zone 3; Because the acquisition pattern of signal segment liquid is consistent with the acquisition pattern of detection segment liquid, again repeat no more.
8) the second association reaction, make semiochemicals and detection zone through first time the material that produces of association reaction within second given time, carry out second time association reaction, produce sample, form a kind of sandwich structure, as the sandwich structure of " fixing seizure antibody 6 or catch aptamer 10-testing protein-signal antibody 8 or signal aptamer 11 ".
9) close application of sample raceway groove 2 and assist gallery 5, after utilizing damping fluid, by detection raceway groove 1, detection zone is completed second time association reaction, remaining material liq is released and is detected raceway groove 1.
10) acquisition and analysis device is utilized to carry out collection analysis to the sample of detection zone.
Micro-raceway groove detection zone e on described biochip, is fixed with the seizure antibody 6 of target substance 7 to be measured or catches aptamer 10.When there being target substance 7 to be measured in sample, the seizure antibody 6 or the seizure aptamer 10 that are fixed on detection zone e will catch target substance 7, can form the sandwich structure to target substance 7 after adding signal antibody 8 or signal aptamer 11 in detection zone.As shown in Figure 2 a and 2 b.
Those skilled in the art can the relevant document understanding sandwich structure of reference antibody prize law, owing to not relating to the improvement of this type of scheme herein, does not repeat them here.
Described signal antibody 8 or signal aptamer 11 refer to be marked with probe molecule 9 can the antibody of target substance 7 specific binding to be measured or aptamer, described probe molecule 9 can be enzyme molecule, fluorescence molecule or other probe molecule 9.
In certain embodiments, concept we be referred to as nanometer sensitization, mainly comprise following two parts content:
(1) at detection zone e decorated nanometer thin layer, utilize nano-material surface effect realize at the fixing more seizure antibody 6 of detection zone e or catch aptamer 10, improve target material capture ability to be measured in sample, thus increase the sensitivity of biochip.
The common concept of nano thin-film is nanometer film, membrana granulosa and dense film.Membrana granulosa is that nano particle sticks together, and there is the film in very tiny gap centre.Dense film refers to that rete is fine and close but crystallite dimension is nano level film.
The Developing Application of nanofiltration (NF) film comparatively reverse osmosis membrane approximately 20 years evenings.20 century 70 JECadotte study NS-300 film, are the beginning of research NF film.
Nanometer film can retain the molecule that relative molecular weight was 300 ~ 100000 (separated material particular diameter is equivalent to 0.3 ~ 100 nanometer), can be used for this case.
" nanometer storage unit " can be expressed as " multiple probe molecule 9 is modified at the cell cube that nano particle is formed ".Wherein the quantity of probe molecule 9 is relevant with the functional group on its surface with the surface area of nano particle.In general, the surface area of nano particle is larger, more in the functional group of its finishing, and to be so fixed on the quantity of nanoparticle surface more for probe molecule 9.But nano particle is unsuitable excessive, the cell cube that excessive nano particle can make signal antibody 8 or the adhesion between signal aptamer 11 and target substance 7 be not enough to signal antibody 8 or signal aptamer 11 are formed stays detection zone, makes detection signal reduce on the contrary.
(2) design nanometer storage unit to increase to the probe molecule 9 of mark on signal antibody 8 or signal aptamer 11.First at nanoparticle surface modified Avidin, and with the coupling of biotinylated probe molecule 9, design different stem grafting methods and increase binding site, make probe molecule 9 in nanoparticle surface enrichment, each nano particle forms the storage unit (as shown in Figure 3) comprising dozens of or more multiprobe molecule 9.
Nano-probe molecule 9 storage unit is modified at on the antibody of target material specific binding to be measured or aptamer, compared to common, single or a small amount of probe molecule 9 is modified on antibody or aptamer, under the same conditions, the former significantly can increase probe molecule 9 fixed amount on a sensor, sensor output signal is amplified, thus significantly improves transducer sensitivity.
Fig. 4 is that the sensitizing effect of three kinds of situations compares (only for luminescence probe): in Fig. 4, (a) is common sandwich structure; B () is modify high loose nanometer thin rete at detection zone e, utilize nanometer layer specific surface effect can fix more seizure antibody 6 at detection zone e or catch aptamer 10, increase and catch probability to sample target substances, improve detection sensitivity; C () is on the basis that detection zone e modifies high loose nanometer thin rete, have employed the nano-probe storage unit shown in Fig. 3, add signal intensity, improve detection sensitivity.
Fig. 5 is the testing result that the sample of different target material concentration is obtained by above-mentioned detection method, and detected object is that brain receives peptide.It is an important indicator of reflection heart failure degree that brain receives peptide BNP (Brain natriuretic peptide), and BNP in blood content only has nanograms/milliliter magnitude, is detected as example with trace BNP in sample, and label probe is luminescence probe.
As can be seen from Figure 5, according to said method, higher accuracy of detection can be obtained.
In another embodiment, get 3 biochips, wherein No. 1 chip catches aptamer 10, No. 2 chips and No. 3 chips are fixing again after detection zone e modifies high loose nanometer thin rete catches aptamer 10 detection zone e is fixing, carries out application of sample according to above-mentioned sample loading alternative to biochip.
First, 3 biochips pass into damping fluid at its a-a ' passage respectively;
Second, 3 biochips pass into the serum sample containing BNP to be measured at its b-b ' passage respectively;
3rd, 3 biochips pass into damping fluid at its a-a ' passage respectively, and serum sample is pushed detection zone, and specific binding occurs seizure aptamer 10 fixing with detection zone under certain condition;
4th, after specific binding has reacted, 3 biochips continue to pass into damping fluid at its a-a ' passage respectively, and serum sample is released detection zone;
5th, the signal aptamer 11 of what the b-b ' passage of No. 1 chip and No. 2 chips passed into that the b-b ' passage of common signal aptamer 11, No. 3 chips passes into is decorated nanometer probe storage unit;
6th, 3 biochips pass into damping fluid at its a-a ' passage respectively, and signal aptamer 11 is pushed detection zone, and signal aptamer 11, with the BNP being trapped in detection zone, specific binding occurs under certain condition;
7th, 3 biochips pass into luminescence reagent at its a-a ' passage respectively, optical detector carries out luminescence to biochip test district and detects.
The testing result of 3 biochips as shown in Figure 6, is 1. No. 1 chip; 2. be No. 2 chips; 3. be the testing result of No. 3 chips.
The sample of different target material concentrations as shown in Figure 5 detects the quantitative Detection results figure of the trace target substance 7 realized by embodiment of the present invention method, as can be seen from the results, at biochip test district decorated nanometer thin layer fixing seizure antibody 6 or seizure aptamer 10 again, then use the signal of the biochip of the signal aptamer 11 of decorated nanometer probe storage unit obviously to be amplified, thus realize the quantitative measurment to trace target substance 7.
By reference to the accompanying drawings the specific embodiment of the present invention is described although above-mentioned; but not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Claims (9)
1., for a pick-up unit for trace target substance in blood sample, it is characterized in that, comprise sample adding device and to sample adding device obtain the sampling and analyzing device that sample detects, wherein said sample adding device comprises:
Detect raceway groove (1), one section of channel feature in its downstream is detection zone (3), and at least leaves detection window at detection zone (3) place; Described detection zone decorated nanometer thin layer, utilizes nano-material surface effect to realize fixing more seizure antibody or seizure aptamer in detection zone, improves target material capture ability to be measured in sample, thus increase the sensitivity of biochip;
Application of sample raceway groove (2), is connected to the Upstream section of detection raceway groove (1) and forms application of sample bypass;
Assist gallery (5), is connected on the detection raceway groove (1) between application of sample raceway groove (2) tie point and detection zone (3), is configured for the bypass of application of sample earial drainage; And detection raceway groove (1) length between application of sample raceway groove (2) and assist gallery (5) is less than the length of detection zone (3);
Signal piping unit, is coupled to and detects raceway groove (1), and be provided with operation valve;
Application of sample pipe-line cell group, is coupled to application of sample raceway groove and assist gallery, and is provided with operation valve group;
Testing pump, is detected the upstream extremity of raceway groove (1), detects auxiliary liquid with pumping by described signal piping unit and corresponding operation valve access;
Sample-adding pump group, by described application of sample pipe-line cell group and corresponding operation valve group access application of sample raceway groove (2), with corresponding pumping sample adding liquid group; And
Control module, connects testing pump, sample-adding pump and operation valve and operation valve group, with the sequence of movement of logic control testing pump, sample-adding pump group and the operation valve that matches, operation valve group;
Described acquisition and analysis device is furnished with the driving mechanism driving it to move to each detection position, detection zone in turn;
Described sampling and analyzing device is the sampling and analyzing device of optics, mated, it comprises one and covers plate (15) with detection window, detection window is wherein similar to the shape of detection zone on optical projection face, and on this optical projection direction, the area of detection window is 1.1 ~ 1.5 times of detection zone area;
Cover on plate (15) and have via hole, selected detection zone is irradiated to for given light beam passes through, and passing through for detection zone folded light beam, under covering plate (15) and making detection zone (3) to be measured be exposed to exciting light (27), and other and its parallel detection district can not be excited by covering, even if or excited its fluorescence to pass on a small quantity, thus the problem that when effectively solving the parallel detection of many raceway grooves, fluorescence disturbs mutually.
2. pick-up unit as claimed in claim 1, it is characterized in that, described driving mechanism is ball-screw screw mechanism.
3. pick-up unit as claimed in claim 1, is characterized in that, described detection raceway groove (1), application of sample raceway groove (2) are identical with the runoff xsect of assist gallery (5), and are plane towards the face of checkout equipment.
4. the pick-up unit as described in claim 1 or 3, is characterized in that, described application of sample raceway groove (2) and assist gallery (5) are all vertical with detection raceway groove (1).
5. pick-up unit as claimed in claim 4, it is characterized in that, described detection raceway groove (1), application of sample raceway groove (2) and assist gallery (5) correspondence comprise the channel groove that is formed in upper surface of substrate and are covered in the upper cover plate (12) of corresponding raceway groove upper surface, and wherein the runoff xsect of channel groove is semicircle or lower surface drift angle arcing square.
6. pick-up unit as claimed in claim 5, it is characterized in that, the width of rebate of described channel groove is 100 μm ~ 1000 μm.
7. pick-up unit as claimed in claim 6, is characterized in that, one detects raceway groove, an application of sample raceway groove and an assist gallery forms an application of sample unit, and the detection raceway groove of multiple application of sample unit is connected in series or and connects.
8. pick-up unit as claimed in claim 7, is characterized in that, and all detection raceway grooves connect are the circular array of common junction centered by inlet and with inlet.
9. pick-up unit as claimed in claim 1, it is characterized in that, the length of described detection zone (3) is 1.5 ~ 3 times of detection raceway groove (1) length between application of sample raceway groove (2) and assist gallery (5).
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