CN1804043A - PCR chip micro-system and method for preparing the same - Google Patents
PCR chip micro-system and method for preparing the same Download PDFInfo
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- CN1804043A CN1804043A CN 200510011180 CN200510011180A CN1804043A CN 1804043 A CN1804043 A CN 1804043A CN 200510011180 CN200510011180 CN 200510011180 CN 200510011180 A CN200510011180 A CN 200510011180A CN 1804043 A CN1804043 A CN 1804043A
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Abstract
本发明提供一种微型聚合酶链式反应(PCR)芯片系统及其制备方法，涉及生物微机电系统技术领域。该PCR芯片包括若干个用于DNA扩增的阱式反应池，反应池通过若干流道与进出液口连接。在芯片上集成微加热器和微传感器，通过温度循环控制系统进行DNA扩增。可以在该芯片上设置微泵，在反应池入口处设置微阀，用于DNA引物的导入及反应池间的隔离。也可以在上述系统中设置荧光激发光源、荧光探测装置及荧光信号检测分析系统进行PCR产物的荧光在位检测。采用MEMS技术加工技术或微模型制备该芯片系统，该生物芯片系统提供了高通量和快速的DNA扩增手段，并具有便于携带、成本低和性能可靠的优点。
The invention provides a miniature polymerase chain reaction (PCR) chip system and a preparation method thereof, and relates to the technical field of biological micro-electromechanical systems. The PCR chip includes several well-type reaction pools for DNA amplification, and the reaction pools are connected with liquid inlets and outlets through several flow channels. Micro-heaters and micro-sensors are integrated on the chip, and DNA amplification is performed through a temperature cycle control system. A micropump can be set on the chip, and a microvalve can be set at the entrance of the reaction pool for the introduction of DNA primers and the isolation between the reaction pools. A fluorescent excitation light source, a fluorescent detection device, and a fluorescent signal detection and analysis system can also be set in the above system to detect the fluorescence in situ of the PCR product. The chip system is prepared by adopting MEMS technology processing technology or micro model, and the biological chip system provides high-throughput and fast DNA amplification means, and has the advantages of portability, low cost and reliable performance.
Description
Technical field
The present invention relates to miniature organism chip system technical field, particularly design of a kind of PCR chip micro-system and preparation method thereof.
Background technology
Polymerase chain reaction (PCR) technology is a kind of common technology of DNA amplification, also is trace/requisite means of trace level detection of biological molecule.PCR is the three warm working cyclees of carrying out sex change, annealing and extension under specific temperature, whenever finishes temperature cycle one time, and the quantity of dna molecular is doubled, and promptly DNA is with 2
nForm increases progressively, and through 20-30 temperature cycle, DNA will be amplified up to a million times.Traditional PCR is tens to finish to 96 orifice plates of several hectolambdas in chamber volume, and the DNA sample behind the PCR need pass through processes such as electrophoresis, fluoroscopic examination, data analysis again, expend the time of several hrs approximately, and total system is huge, complicated operation.The quantitative fluorescent PCR reaction is the new nucleic acid quantification detection technique of a class of development in recent years, this technology is used the fluorescent label DNA probe on the pcr chip of design, according to the principle of fluorescent quenching, by directly the detection of change in fluorescence amount in the reaction being come the result of analytical reaction.It not only has the hypersensitivity of common PCR reaction, and because the application of fluorescent probe, the variation that can pass through fluorescent signal in the fluorescence detecting system direct detection pcr amplification reaction process is to obtain quantitative results.
Advantages such as one of the miniaturization of bio-analysis instrument and process and integrated important directions that has become research fields such as 21 century life science, microtronics, chemistry, chip micro-system have high-throughput, highly sensitive, cost is low, experimental result is reliable, easy handling.Miniature analytical system simple to operate is detection air, food, water and Working environment safety fast.The doctor can diagnose out patient's disease at the chip of size as the indoor palm of office in several minutes, suit the remedy to the case.The array assay laboratory can fast and reach the screening new drug a large amount of synthesizing, and quickens the exploitation of new drug.Portable quantitative fluorescent PCR chip micro-system is applicable to the real-time monitoring of multiple virus, bacterium and several genes rearrangement, sudden change and the damaged evaluation of various biologies such as the mankind, animal and plant, has wide practical use in national defence early warning, disaster prevention, clinical disease diagnosis, Human genome group analysis, gene pleiomorphism evaluation, the screening of animal and plant genovariation etc.
Summary of the invention
The purpose of this invention is to provide a kind of high-throughout PCR chip micro-system that is used for trace/trace biomolecular monitoring, this chip system can carry out the amplification of thousands of kinds of samples simultaneously.
Another object of the present invention is integrated fluorescent signal check and analysis systems, directly carries out the fluorescence detection on the throne of pcr amplification product.
For achieving the above object, the present invention takes following technical scheme: a kind of PCR chip micro-system, comprise polymerase chain reaction (PCR) chip and the heat circulating system that are used for DNA cloning, it is characterized in that: PCR chip comprises substrate chip and chip capping, fluid inlet, liquid outlet, runner and several to thousands of reaction tanks are arranged on the chip, and liquid inlet and outlet is connected with each reaction tank by runner; Heat circulating system comprises micro-heater, micro sensor and temperature controlling system, micro-heater and micro sensor preparation can adopt sputter, evaporation, electron beam deposition method to prepare the micro-heater and the micro sensor of platinum, aluminium, gold copper-base alloy in substrate chip or chip capping.Controlling System is core with the micro-chip and links to each other with micro sensor with micro-heater that Controlling System comprises circuit and corresponding software designs thereof such as A/D conversion, pwm circuit, linear amplifier circuit, peripheral circuit, data-carrier store.
On above-mentioned pcr chip micro-system, can be provided for importing the Micropump of dna primer, Micropump can be that valve mechanical pump, valve free pump are arranged, adopt piezoelectricity, static, electromagnetism, gas heat, pneumatic, bimetal, electrochemical means to drive Micropump, Micropump can adopt driving gas and introduce liquid or directly drive the work of liquid dual mode.Can also little valve be set in each reaction tank ingress of above-mentioned pcr chip, be used to isolate each reaction tank, little valve can be mechanical little valve or the little valve of on-mechanical, adopts the little valves of mode driving device such as piezoelectricity, static, electromagnetism, gas heat, pneumatic, bimetal, electrochemistry.
It is chip material that chip can adopt silicon and glass, described chip can be selected the micromachining technology preparation, described preparation method is included in machining 3 D reaction tank on the substrate material, runner, liquid in-out mouth, Micropump and little valve system, adopt transparent polymkeric substance or glass as the chip capping, drive fluid hole on chip capping or substrate chip, the bonding encapsulation is aimed in the chip capping with substrate chip.
Chip can also adopt polymer materials to utilize microscopic model technology processing and preparing, and described preparation method comprises negative norm tool of preparation, shaping three-dimensional polymer chip structure on mould then, and method comprises moulding method, pressure sintering, injection moulding.Adopt transparent polymkeric substance or glass as the chip capping, drive the liquid in-out mouth on chip capping or substrate chip, the bonding encapsulation is aimed in the chip capping with substrate chip.
Can be on miniature pcr chip integrated encapsulation fluorescence in-place detection system, the fluorescence in-place detection system comprises dot matrix type excitation light source, dot matrix type photodetector and fluorescent signal data handling system.Excitation light source and photodetector lattice position are corresponding one by one with above-mentioned reaction tank.Described excitation light source can be blue-ray LED or other type excitation light source, and described photodetector can be silicon or compound semiconductor light electric diode or photomultiplier, and the fluorescent signal data handling system is core with the micro-chip.
Above-mentioned pcr chip micro-system need be integrated encapsulation, links to each other with computer by interface, and by analysis software control total system, described chip micro-system can select for use Taqman and SYBR Green molecular probe to carry out the amplification of DNA.
The preparation method one of polymerase chain reaction array chip micro-system, its step comprises:
(1) the compound mask of deposit on substrate chip, mask material can be silicon oxide, silicon nitride, photoresist material, metal etc.;
(2) utilize mask plate to carry out photoetching on mask, formation comprises liquid in-out mouth, reaction tank, runner, Micropump, the isostructural transition diagram of little valve, selects the quantity of mask plate according to the depth situation of structure;
(3) wet etching or dry etching silicon or glass-chip, the three-dimensional structure of formation liquid in-out mouth, reaction tank, runner, Micropump, little valve figures;
(4) corrode or etch away remaining mask on the substrate chip, deposition one deck does not suppress the thin-film material of PCR reaction on chip, as SiO
2
(5) deposit metal electrodes on substrate chip or chip cover plate forms micro-heater and micro sensor, and drive the fluid oral pore on chip, and the chip of finishing is aimed at bonding with the chip capping, and bonding method comprises anode linkage and polymer-bound etc.
The preparation method two of miniature PCR chip system, its step comprises:
(1) make the negative norm tool, form the complementary structure of substrate chip, moulding stock comprises SU-8 glue, polymkeric substance, silicon, metal etc., adopts micromachining technology, LIGA technology, thick resist lithography technology to prepare mould;
(2) growth one deck release materials on mould is a chip material with polymkeric substance such as plastics, polydimethylsiloxanes, adopts the three-dimensionally shaped method of polymer materials to form desired shape, as moulding method, pressure sintering, injection moulding, peels off chip and obtains required chip;
(3) adopt polymkeric substance or glass as the chip capping, splash-proofing sputtering metal forms micro-heater and micro sensor in substrate chip or chip capping, drives liquid outlet on chip into;
(4) substrate chip is aimed at bonding with the chip capping, can realize the encapsulation of chip by reactive ion etching technology activated polymer and glass surface, and improve the wetting ability of chip surface.Also can adopt with the polymer-bound technology and realize Chip Packaging.
Technique effect of the present invention: this chip system is by design and preparation, integrated micro heat circulating system, integrated Micropump and little valve and the realization of fluorescence in-place detection system of array reaction tank, the primary process of system works is: in the reaction tank of fluorescently-labeled different dna probe point samples on chip, can design the quantity of reaction tank as required; The operation Micropump drives the sampling primer and enters in the chip reaction tank; Temperature circulatory system work is carried out the PCR reaction by program setting; After reaction finishes, fluorescence detecting system detection reaction product, system is according to the position and the strong and weak judgement reaction result of fluorescence.
This integrated micro-system can be finished the detection and the discriminating of biological species in 60 minutes, embodied system's characteristics fast.On a chip, can design thousands of reaction tanks, embody the high-throughout characteristics of chip system.System after integrated is more bigger than a notebook computer, has embodied the portable of system.This chip system is applicable to fluorescent probes such as Taqman, SYBR Green, molecular beacon, and system itself promptly constitutes check section office, can be widely used in the near real-time quantitative monitoring of various trace/trace amount DNAs, protein, virus, bacterium.
Description of drawings
The integration mode synoptic diagram of the miniature PCR chip of Fig. 1 system;
Another integration mode synoptic diagram of the miniature PCR chip of Fig. 2 system;
Fig. 3 silicon or glass micromachining technology prepare the process flow diagram of chip;
The electron scanning micrograph of the array chip of processing on Fig. 4 silicon chip;
Fig. 5 microscopic model technology prepares the process flow diagram of chip;
Fig. 6 microscopic model technology prepares the electron scanning micrograph of array polydimethylsiloxanechip chip;
The structure of Fig. 7 PIN photodetector is thrown the face synoptic diagram.
Embodiment
Pcr chip micro-system of the present invention comprises PCR chip and the heat circulating system that is used for DNA cloning, PCR chip comprises liquid in-out mouth, runner and several to thousands of trap formula reaction tanks, and liquid inlet and outlet is connected with each reaction tank by runner.On one several square centimeters chip, can design several thousand and receive the reaction tank that rises volume, utilize the widow of biomolecules to examine mandarin orange acid polymorphism theory and in reaction tank, carry out different PCR reactions.Above-mentioned reaction tank quantity determines according to needs, the reaction tank volume receive liter (nL) with milliliter (mL) between, reaction tank can be square, rectangle, circle, shape such as trapezoidal, flow channel cross-section can be square, rectangle, semicircle, shape such as trapezoidal.
Heat circulating system comprises micro-heater, micro sensor and temperature controlling system, micro-heater and micro sensor can be Pt, Al, Au constant resistance material, adopt sputter, evaporation, the preparation of electron beam deposition method, micro-heater and micro sensor preparation are in chip back or chip capping, the size and the resistance of micro-heater determine that according to heating power heating power is more than 10mW.Micro-heater and micro sensor are connected in the outside temperature Controlling System, are used for the quick switching process of temperature on the control chip.Controlling System is core with the micro-chip, comprise circuit and corresponding software designs thereof such as A/D conversion, pwm circuit, linear amplifier circuit, peripheral circuit, data-carrier store, by computer program and algorithm control single chip computer and width modulation (PWM) circuit, power circuit is regulated heater heats voltage, to the chip control of heating and freeze, realize the integrated of PCR reaction process.Heat circulating system can also adopt semiconductor cooler and design radiator element and carry out system's cooling on chip.The final system temperature rise rate is between 1-15 ℃/s, and rate of temperature fall is between 1-10 ℃/s.
Integrated Micropump and little valve on chip, Micropump are used to drive dna primer and flow into chip, avoid forming bubble and dead band in chip, and Micropump can be that valve mechanical pump and micro valveless pump are arranged, and micro valveless pump can comprise miniature jet pump and minisize diffusion pump.Inlet at each reaction tank of chip is provided with little valve, is used to prevent that liquid rushes down in the reaction tank outward, avoids the interior liquid of each reaction tank mixed, and miniature valve can be micro-mechanical valve or the little valve of on-mechanical, and the on-mechanical valve comprises passive valves and drain valve.Micropump and little valve can adopt modes such as piezoelectricity, static, electromagnetism, gas heat, pneumatic, bimetal, electrochemistry to drive.Micropump can directly drive liquid and flow into reaction tank, also can form negative pressure and import liquid in chip by driving gas.
Miniature PCR chip of the present invention can be realized by following making embodiment:
Scheme one: silicon micro-machining technology, work flow are seen synoptic diagram 3
(1) shown in Fig. 3-a, the compound mask of deposit on the silicon substrate 1 is respectively mask 1 and is mask 2 13, and mask material can be silicon oxide, silicon nitride or other material, as photoresist material, metal mask etc.
(2) shown in Fig. 3-b, utilize mask plate 1 photoetching on mask 2 13, form the structure graph that comprises reaction chamber 5 and Micropump 6.
(3) shown in Fig. 3-c, utilize mask plate 2 photoetching on mask 1, formation comprises runner, diffuser valve structure graph.
(4) shown in Fig. 3-d, wet method or dry etching silicon chip form reaction chamber 5 and Micropump 6 structures, and concrete depth of corrosion is determined according to performance index.
(5) shown in Fig. 3-e, remaining mask 2 13 on the silicon chip to be removed, wet method or dry etching silicon chip etch runner and diffuser valve structure, and concrete etching depth is determined according to performance index.
(6) shown in Fig. 3-f, remaining mask corrosion on the silicon chip is fallen, and on silicon substrate 1 or cover glass 2 the splash-proofing sputtering metal electrode, form well heater 7 and transmitter 8.
(7) be shown in as Fig. 3-g and drive the fluid oral pore in the chip capping into, can adopt laser boring, ultrasonic punching or corroding method.
(8) silicon chip that etching is intact is aimed at bonding with capping shown in Fig. 3-h, and bonding method comprises anode linkage and polymer-bound etc.
Fig. 4 is given in the photo of the array chip structure scanning electronic microscope that processes on the silicon chip.
Scheme two: microscopic model technology processing array chip, work flow is seen Fig. 5, concrete steps are:
(1) shown in Fig. 5-a, at first be to make negative norm tool 14, its technological process is for photoetching on silicon chip and erode away the complementary structure of chip, and the process of processing silica-based pcr chip in concrete steps and the scheme one is identical.Mould 14 also can adopt other material (as SU-8, metal etc.) to utilize thick resist lithography, LIGA technology to make.
(2) shown in Fig. 5-b, (as PDMS, PF, PE, PMMA etc.) are chip material 15 with polymer materials, adopt the three-dimensionally shaped method of polymer materials, on mould, make the pcr chip 15 of polymer materials as working methods such as moulding method, pressure sintering, LIGA technology.
(3) moulding method prepares chip method and comprises: at first in mould 14 long-living length with apply one deck releasing agent, so that polymer chip is easy to peel off from mould; With polymkeric substance and solidifying agent thorough mixing 14 thereof, and under the certain vacuum condition, outgas, remove the air in the mixture; Mould is positioned in the tray, and the thickness of dish is consistent with required chip thickness; The blended polymkeric substance is cast on the mould, and does the further degassing; Cure polymer under certain temperature and time conditions, the decision of solidification value and basis of time material character is (as Fig. 5-b); Polymer-stripping from the mould obtains and negative norm tool pattern complementary chip structure 15 (shown in Fig. 5-c);
(4) pressure sintering prepares chip and need be equipped with hot-press arrangement, and its crucial preparation method is: prepare a mould 14 (materials such as metal, silicon) (Fig. 5-a); In hot-press arrangement, polymer matrix film is heated to softening temperature; By on mould, applying certain pressure, and keep certain hour, can on polymer matrix film, suppress and the concavo-convex complementary chip structure of mould (Fig. 5-b); Under the condition of pressurization, mould is cooled off the back demoulding with substrate, obtain required microstructure 15 (Fig. 5-c), sputter well heater 7 and transmitter 8 on chip;
(5) adopt polymkeric substance or glass as chip capping 2, and drive the fluid oral pore into, can adopt laser boring, ultrasonic punching or corroding method (Fig. 5-d).
(6) chip is aimed at bonding (Fig. 5-e), bonding can be realized the encapsulation of chip by reactive ion etching system activated polymer and glass surface with capping.Also can adopt polymer-bound to realize the encapsulation of chip.
Fig. 6 provides the electron scanning micrograph of microscopic model technology processing array chip.
Integrated encapsulation fluorescence in-place detection system in the array chip system of miniature polymerase chain reaction, the fluorescence in-place detection system comprises fluorescence excitation light source, photodetector and fluorescent signal data handling system.The light source that is used for fluorescence excitation can be blue-ray LED or other type excitation light source, blue-ray LED can adopt GaN/InGaN LED, also can adopt other type compound semiconductor LED, the LED emission wavelength is 400nm-500nm, and the excitation light source position is corresponding one by one with above-mentioned reaction tank.Adopt metal organic-matter chemical gas deposition (MOCVD) method heterogeneous growing GaN/InGaNLED on Sapphire Substrate.GaN/InGaN LED also can adopt the reverse installation process preparation, and light is sent from the sapphire face.The device that is used for fluoroscopic examination can be photodetector or other type fluorescent scanning system, and photodetector can be silicon or compound semiconductor light electric diode or photomultiplier, and the silicon based opto-electronics detector comprises PIN, PINN
+Photorectifier, avalanche optoelectronic secondary light, chip scanner can be laser co-focusing chip scanner or CCD chip scanner, and the position of photodetector is corresponding one by one with the reaction tank position.The data handling system of fluorescent signal is core with the micro-chip and links to each other with Electro-Optical Sensor Set that system comprises fluorescent signal Acquisition Circuit or hyperchannel fluorescent signal logic identification systems such as data processing database, signal acquiring system, image analysis and data handling system, image processing and data extract software etc., output signal amplification, anti-mixing, filtering.
Chip system with reference to figure 1 is integrated packaged type 1, and whole pcr chip micro-system comprises substrate chip 1, capping chip 2, photodetector 3, fluorescence excitation light source 4, reaction tank 5, Micropump 6, micro-heater 7, micro sensor 8, temperature controlling system 9, fluorescent signal treatment system 10, Computer Processing Controlling System 11.System also can adopt the form of Fig. 2 to integrate, substrate chip is a photodetector 3, reaction tank 5 and Micropump 6 are set on the capping chip 2, micro-heater 7 and micro sensor 8 are arranged on the photoelectric detector chip 3, and system finishes the detection task under the control of temperature controlling system 9, fluorescent signal treatment system 10 and Computer Processing Controlling System 11.
Chip is integrated packaged type 1: promptly at preparation feedback chamber, substrate chip front, runner, liquid in-out mouth, Micropump and little valve, prepare micro-heater and micro sensor at the substrate chip back side, preparation blue-ray LED and the capping of double as chip on Sapphire Substrate, another chip prepares photodetector, and low-temperature bonding encapsulates each chip.Chip integration packaged type 2 " on substrate, prepare micro-heater, micro sensor and photodetector, process chamber, runner, liquid in-out mouth, Micropump and little valve on another transparent chips, blue-ray LED is bonded in the capping upper surface.Before encapsulation was carried out, chip internal-surface was coated with and is coated with the material of not restraining the PCR reaction, adopted technology such as anode linkage, polymer-bound, hot pressing to realize encapsulation then, and this encapsulation should be satisfied the requirement of hydraulic seal.Dielectric material in the polymer-bound can be a sticking and material such as Resins, epoxy, benzocyclobutane (BCB), polyimide, photoresist material.
One of mode that is used for the fluorescent signal detection of foregoing invention is for adopting silicon to prepare the PIN photodetector, and Fig. 7 is that the structure of PIN photodetector is thrown the face synoptic diagram, and its basic preparation process is:
(1) adopt high resistant monocrystalline substrate sheet, the design photodiode array is corresponding one by one with quantity with the position of chip reaction tank, and photosensitive diameter is consistent with the reaction tank size.
(2) inject formation depletion region and the ion implantation formation of n (p) type p/n knot by the field of p (n) type.
(3) reduce PIN device interior impurity and defective with back side impurity-absorbing technique, improve carrier lifetime, reduce the device dark electric current.
(4) depositing metal 16, form metal lead wire by caustic solution, and constitute ohmic contact with the diode interface.
(5) growth of passivation film 18 and optical filtering, anti-reflection multilayer complex films 17, structure of composite membrane can stop effectively that exciting light disturbs, and increase fluorescence intensity to be measured, reduce optical loss.
One of the fluorescence excitation mode that is used for that foregoing invention proposes is to adopt blue light GaN/InGaN LED, and the basic skills of its preparation is:
(1) selects for use sapphire as substrate material, and adopt the required heterojunction material of metal organic-matter chemical gas deposition (MOCVD) method deposit.
(2) adopt the non-Doped GaN film of MOCVD growth 1-2 μ m.
(3) the periodic superlattice heterojunction structure of the InGaN/GaN of MOCVD grow doping, it is 400nm-500nm (fluorescence exciting wavelength) that control In concentration makes the LED emission wavelength.
(4) depositing metal and corrosion form electrode on the chip.
(5) adopt reverse installation process to prepare GaN base LED, light is sent from the sapphire face, thus the easier realization system integration on technology.
Chip micro-system of the present invention has receives the array reaction chamber that rises volume, and the micro-heater and the micro sensor that are integrated on the chip constitute a more complete integrated chip under the control of temperature controlling system.Integrated Micropump and little valve have improved the reliability and the operability of system, and that system-level integrated fluorescence in-place detection system has really realized is portable, high-throughput, at a high speed, low-cost and intelligentized biological detection micro-system.
The present invention relates to fields such as microtronics, photoelectronics, control automatically, computer, biomedicine, be the achievement in research of a multidisciplinary intersection, this detection system is with a wide range of applications in biomedicine, environmental monitoring, food quality detection, emergency incident and national defence field.
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