CN101614717B - Micro-channel unit module, fluid concentration gradient generator and flow resistance measurer - Google Patents
Micro-channel unit module, fluid concentration gradient generator and flow resistance measurer Download PDFInfo
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Abstract
The invention relates to a functional micro-channel unit module, a fluid concentration gradient generator and a flow resistance measurer. The micro-channel unit module relates to a fluid-shunting module, a fluid-converging module, a fluid variable resistance module, a fluid-collecting module, a fluid speed-adjusting module, and the like. Suitable micro-channel unit modules can be selected as required to construct different micro-flow network systems, such as the flow resistance measurer for measuring the flow resistance of fluid, a fluid linearity concentration gradient generator for operating the fluid and generating a concentration gradient of the fluid, a fluid arbitrary concentration gradient generator, and the like, thereby greatly shortening the preparation time of a concentration gradient device, lessening the reliance on micro-processing equipment, randomly replacing a damaged module in a modularized system and keeping the stability of the system. The invention can be widely applied to physical, chemical and biological fields.
Description
Technical field
The present invention relates to the chip and the application thereof that are consisted of by micro-channel unit, particularly micro-channel unit module, fluid concentration gradient generator and flow resistance measurer.
Background technology
Micro-fluidic powerful instrument as handling micro fluid has obtained using more and more widely in chemistry, biology, medical science.Micro-fluidic characteristics are to be prepared into the size of micron by the pipeline with the flow warp, thereby can be confined to the path of whole flow warp on a small chip micro-fluidic chip technology that Here it is.In micro-fluidic, fluid is because of size decreases, and mobile state is the characteristics of laminar flow, can describe with more accurate physical equation.In addition, the increase of the specific surface area of also bringing fluid of diminishing of size.Large specific surface area is conducive to increase the efficient that fluid carries out biology, chemical reaction, improves sensitivity.At last, little size is conducive to whole micro fluidic device miniaturization, and can realize high flux, multichannel synchronous reaction.
Concentration gradient has very important meaning in biology, the migration of it and cell, the oriented growth of neuron axon, embryo's the physiology courses such as growth are closely related.In biosome, some functional signaling molecules are different as growth factor, hormone molecule at Different Organs, in-house content, and even in same organs, content is also along with the time changes.This is because the metabolism of life, signal conduction etc. are complicated physiology courses, adds physics, chemical action, and the concentration gradient of the actual functional molecular that produces is all nonlinear.Therefore, if the concentration gradient in in-vitro simulated life entity need to have such device can produce needed concentration gradient.
The device for preparing concentration gradient with micro-fluidic chip has had many examples in the world.Systematic summary on document [T.M.Keenan and A.Folch, Lab Chip, 2008,8,34-57].Before microflow control technique occurs, early stage device utilization be to place a diffuse source in gel or solution, the diffusion by functional molecular forms concentration gradient.Although this device is simple in structure, easily realize, be difficult to form stable gradient, the gradient that not only forms is difficult to quantize, and can not keep for a long time.Optimization to this types of devices can only produce single gradient, extends the time that concentration gradient is kept.With micro-fluidic method, can greatly improve the ability that produces complicated concentration gradient.After the passing through two fluid streams and merge of T-shape, the diffusion of carrying out molecule at the interface produces gradient [patent US0042712A1], to repeatedly separation, the mixing in a micro-fluidic network of two strands of solution that pass through initial variable concentrations of pyramid shape, form at last accurate, stable concentration gradient [patent US7314070B2, US0129336A1 etc.], micro-fluidic its powerful ability aspect the manipulation fluid that fully shown.At present, utilize the principle of micro-fluidic generation concentration gradient to have a lot, except mixing separating of the diffusion that utilizes molecule above-mentioned and fluid, also have real-time monitoring injection port place sample flow, the length of the different streams of design regulates and controls the blending ratio of fluid in fluid network.The concentration gradient of the generation that these devices have is fairly simple, although have complicated can only produce single gradient, very difficult generation is complexity but also gradient that can real-time change not only.In addition, the above-mentioned micro-fluidic chip of mentioning is all integrated.In integrated process, the micro-fluidic network structure that the gradient that produce is corresponding is fixed on above chip, thereby causes the gradient kind that produces limited, and each gradient all will redesign new structure.And in case certain part in the fluid network structure is damaged, whole device just can't continue to use, and need to again prepare chip.This will extend undoubtedly the time of experiment and improve the cost of experiment.
Integrated method has been brought certain difficulty to the pressure in Real-Time Monitoring miniflow network except the arbitrariness and real-time that affect concentration gradient.Pressure in monitoring miniflow network just can obtain the information of flow resistance in network, thereby can raise at little yardstick the flow direction and the flow of flow control body.This plays a very important role in the shearing force that produces concentration gradient, adjusting fluid.Monitoring about pressure at present can utilize the pressure transducer of piezoelectric with integrated method preparation, but can run into complicated micro-processing technology, and the consistency problem of material [patent US6986649B2].And the variation that utilizes gas volume indicates the method for pressure at patent US6575026B1, and US6843121B1 is existing to be described.The method is simple, but owing to being integrated preparation adding what consider man-hour, thereby can only measure the pressure of fixed position.
Summary of the invention
Purpose of the present invention is in order to overcome the shortcoming of above-mentioned microchannel chip, the fluid channel modularization that provides and build micro-fluidic fluid network; The micro-channel unit module that contains different micro-channel units is provided, and they are assembled into the fluid concentration gradient generator that can produce linear concentration gradient and the flow resistance measurer of the flow resistance in Real-Time Monitoring miniflow network.Modular structure is simple, can scale prepare, and the concentration gradient of generation can satisfy the human internal environment of Simulation of Complex, has very large using value.
Technical scheme of the present invention is as follows:
Micro-channel unit module provided by the invention, the element and the planar substrates that are had the micro-recesses unit by a surface form; The surface with micro-recesses unit of described element and the described planar substrates formation micro-channel unit module that is bonded into one;
Described micro-channel unit module is fluid diverter module A, the micro-channel unit of this fluid diverter module A is comprised of the n+1 bar linearity delivery channel that the linear input duct of n bar and a linear transitions runner by vertical placement with it are connected with the linear input duct of this n bar, described n is the positive integer more than or equal to 1, and the cross-sectional area of described linear input duct, linear delivery channel and linear transitions runner equates; Perhaps
Described micro-channel unit module is fluid diverter module B, and the micro-channel unit of this fluid diverter module B forms by converging mutually the linear fluid channel that the m sliver transvers section area be communicated in linear fluid channel port equates, the linear fluid channel of this m bar is dispersion shape and arranges; It is the fluid course entrance that the linear fluid channel of this m bar is converged communications ports mutually, and the other end of the linear fluid channel of this m bar is the fluid course outlet, and described m is the positive integer more than or equal to 1; Perhaps
Described micro-channel unit module is that fluid converges module, the micro-channel unit that this fluid converges module is comprised of the n bar linearity delivery channel that the linear input duct of n+1 bar and a linear transitions runner by vertical placement with it are connected with the linear input duct of this n+1 bar, described n is the positive integer more than or equal to 1, and the cross-sectional area of described linear input duct, linear delivery channel and linear transitions runner equates; Perhaps
Described micro-channel unit module is fluid variable resistance module, the micro-channel unit of this fluid variable resistance module forms by being the linear fluid channel that cross-sectional area that serpentine shape arranges equates, a fluid course entrance and O-Y runner exit on this linearity fluid channel, described Y is the positive integer more than or equal to 1; Perhaps
Described micro-channel unit module is the fluid collection module, the micro-channel unit of described fluid collection module is that the linear fluid channel of parallel arrangement becomes with the linear fluid channel that the both ends section tilts respectively laterally by s bar interlude, the cross-sectional area of described linear fluid channel is equal, and described s is the positive integer more than or equal to 1; Perhaps
The micro-channel unit of described fluid collection module forms by converging mutually the linear input duct that the t sliver transvers section area be communicated in a linear delivery channel equates, the cross-sectional area of this linear delivery channel is more than or equal to any linear input duct cross-sectional area, and described t is the positive integer more than or equal to 1; Perhaps
Described micro-channel unit module is the fluid speed adjusting module, and the linear fluid channel of the micro-channel unit of this fluid speed adjusting module is the long-pending linear fluid channel that is linear change of flow channel cross-section.
Fluid concentration gradient generator provided by the invention is the linear concentration gradient generator; This fluid concentration gradient generator is comprised of a stoste driving pump, a dilution driving pump, an X1 fluid diverter module and a fluid collection module, and X1 is the positive integer more than or equal to 1;
The two-lines input duct entrance of described first fluid diverter module is connected with described stoste driving pump and dilution driving pump respectively;
Three linear delivery channel outlets of described first fluid diverter module are connected with three linear delivery channel entrances of second fluid diverter module respectively; By that analogy, the linear delivery channel outlet of the n bar of described X1 fluid diverter module is connected with the linear fluid channel entrance of n+1 bar respectively; The linear fluid channel outlet of the n+1 bar of described X fluid diverter module is connected with the linear fluid channel entrance of described fluid collection module respectively;
The micro-channel unit of described fluid collection module is that the linear fluid channel of parallel arrangement becomes with the linear fluid channel that the both ends section tilts respectively laterally by s bar interlude, and the cross-sectional area of described linear fluid channel equates;
Perhaps
The micro-channel unit of described fluid collection module forms by converging mutually the linear input duct of the t sliver transvers section area be communicated in a linear delivery channel, and the cross-sectional area of this linear delivery channel is more than or equal to any linear input duct cross-sectional area.
Fluid concentration gradient generator provided by the invention is fluid any concentration gradient generator, this fluid concentration gradient generator converges module by an original solution driving pump, a dilution driving pump, 2 fluid diverter module B, X2 fluid variable resistance module, an X2 fluid and a fluid collection module forms, and X2 is the positive integer more than or equal to 2;
The micro-channel unit of described fluid diverter module B forms by converging mutually the linear fluid channel that the m sliver transvers section area be communicated in linear fluid channel port equates, the linear fluid channel of this m bar is dispersion shape and arranges; It is the fluid course entrance that the linear fluid channel of this m bar is converged communications ports mutually, and the other end of the linear fluid channel of this m bar is the fluid course outlet;
The micro-channel unit of described fluid variable resistance module forms by being the linear fluid channel that cross-sectional area that serpentine shape arranges equates, a fluid course entrance and a fluid course outlet are arranged on this linearity fluid channel;
The micro-channel unit that described fluid converges module is comprised of 1 delivery channel that 2 input ducts and 2 input ducts of a transition runner and this by vertical placement with it are connected; The cross-sectional area of described input duct, linear delivery channel and transition runner equates;
The micro-channel unit of described fluid collection module is that s bar interlude is the linear fluid channel of parallel arrangement and the linear fluid channel composition that the both ends section tilts respectively laterally, and the cross-sectional area of described linear fluid channel equates;
Perhaps
The micro-channel unit of described fluid collection module is served as reasons mutually and to be converged the linear input duct of the t sliver transvers section area that is communicated in a linear delivery channel and form, and the cross-sectional area of this linear delivery channel is more than or equal to any linear input duct cross-sectional area;
Described two fluid diverter module B are respectively original solution diverter module and dilution diverter module, the fluid course entrance of this original solution diverter module is connected with the original solution driving pump, and the fluid course entrance of dilution diverter module is connected with the dilution driving pump;
Described original solution diverter module and dilution diverter module have respectively a fluid course outlet to be connected with the linear input duct of described fluid collection module respectively;
All the other r-1 of described dilution diverter module fluid course outlets are connected with r-1 fluid input duct entrance that converges module, and any one fluid course outlet during this r-1 of described dilution diverter module fluid course exports only is connected with a fluid input duct entrance that converges module;
All the other r-1 of original solution diverter module fluid course outlets first are connected with the fluid course entrance of r-1 fluid variable resistance module, the fluid course outlet of this r-1 fluid variable resistance module is connected with r-1 fluid input duct entrance that converges module again, and any one fluid course outlet during this r-1 of described original solution diverter module fluid course exports only is connected with a fluid input duct entrance that converges module;
R-1 fluid delivery channel that converges module is connected with the input duct of fluid collection module respectively.
Flow resistance measurer provided by the invention converges module by an original solution driving pump, diverter module, one, and two fluid variable resistance modules and a miniflow pipeline to be measured form;
The micro-channel unit of described diverter module is comprised of 2 linear delivery channels that 1 linear input duct and 1 the linear input duct of a linear transitions runner and this by vertical placement with it are connected; The cross-sectional area of described linear input duct and linear delivery channel equates;
The described micro-channel unit that converges module is comprised of 1 linear delivery channel that 2 linear input ducts and 2 the linear input ducts of a linear transitions runner and this by vertical placement with it are connected; The cross-sectional area of described linear input duct and linear delivery channel equates;
The micro-channel unit of described fluid variable resistance module forms by being the linear fluid channel that cross-sectional area that serpentine shape arranges equates, this linearity fluid channel only has 1 runner entrance;
Described miniflow pipeline to be measured is by a linear fluid runner with a fluid course entrance and a fluid course outlet;
The fluid input duct of described diverter module is connected with the original solution driving pump, and 2 fluid delivery channels of this diverter module are connected with the runner entrance of a fluid variable resistance module and the fluid course entrance of miniflow pipeline to be measured respectively;
Described 2 fluid input ducts that converge module are connected with the fluid course outlet of miniflow pipeline to be measured and the runner entrance of another fluid variable resistance module respectively;
Fluid pressure in the fluid variable resistance module that the fluid pressure of the fluid course porch of miniflow pipeline to be measured equals to be connected with diverter module;
The fluid pressure in the fluid course exit of miniflow pipeline to be measured equal with converge the fluid variable resistance module that module is connected in fluid pressure;
Difference between fluid pressure in two fluid variable resistance modules is the fluid pressure reduction value in miniflow pipeline to be measured;
The ratio of the fluid delivery rate that the fluid pressure reduction value in miniflow pipeline to be measured and original solution driving pump are set is the flow resistance value of fluid.
The preparation of micro-channel unit module of the present invention utilizes soft lithographic technique to complete; At first, with the described pattern of L-Edit Software for Design, and print by film printer; Then described pattern is carried out lithography process; Because described pattern area is little, can be made in simultaneously on the silicon chip of 3 cun areas; What photoresist used is the negative glue of the thick type of SU-8 of MicroChem company.Through spin coating, front baking, exposure, after baking, develop after, described pattern is just carried by the photoresist on silicon chip; The silicon chip with photoresist that processes is gone up dimethyl silicone polymer, and (poly (dimethylsiloxane) PDMS) carries out duplicating molded; Then the baking oven at 80 degree toasted 1 hour, and PDMS has just formed solid; This solid is flexible, can take off above silicon chip; Take PDMS off, pattern has just been transferred to above PDMS, and pattern at this time is to be recessed among PDMS; At last, carry out the surface plasma oxidation processes with PDMS with through the microslide that cleans, after processing, both just can very firmly be bonded together, and the pattern that is recessed in PDMS has also just formed micro-fluidic pipeline between PDMS and slide.
Characteristics of the present invention are:
1, designed some functional micro-channel unit modules, these modules can be carried out shunting, converge, collect, regulate and control the functions such as flow resistance, speed governing;
2, the method for application module builds microfluidic system; The advantage of modular microfluidic streaming system is the preparation time that can greatly reduce the concentration gradient device, reduces the dependence to little process equipment, and the module of damaging in the replacement module system at any time, the stability of keeping system.
3, used the some of them module construction and produced the concentration gradient that the device of concentration gradient produces and have arbitrariness and real-time, this is that integrated device can't be realized.
4, in the measurement miniflow network that builds, the device of flow resistance can be measured actual flow resistance very easily.
Description of drawings
Fig. 1-1 is the schematic diagram of the micro-channel unit module of difference in functionality to Fig. 1-10;
Fig. 2 is the structural representation of fluid variable resistance module;
Fig. 3 is a kind of structural representation of the fluid concentration gradient generator for generation of linear concentration gradient;
Fig. 4-1 to Fig. 4-4 are the fluorescence intensity figure of the linear concentration gradient of generation;
Fig. 5 is the structural representation for generation of the linear concentration gradient generator of any and real-time change;
Fig. 6-1 to Fig. 6-4 are the fluorescence intensity figure of a complicated concentration gradient of generation;
Fig. 7 is the fluorescence intensity figure of the concentration gradient of real-time change;
Fig. 8-1 to Fig. 8-4 are for realizing the fluorescence intensity figure of the concentration gradient of real-time change with another kind of method;
Fig. 9 is the structural drawing for the fluid any concentration gradient generator of the pressure of measuring in real time the miniflow network and flow resistance.
Figure 10 is the comprehensive schematic diagram (same Fig. 1-1 is to Fig. 1-10) of micro-channel unit module.
Embodiment
Micro-channel unit module of the present invention can be divided into fluid diverter module A and fluid diverter module B; The micro-channel unit of described fluid diverter module A is comprised of the n+1 bar linearity delivery channel that the linear input duct of n bar and a linear transitions runner by vertical placement with it are connected with the linear input duct of this n bar, described n is the positive integer more than or equal to 1, and the cross-sectional area of described linear input duct, linear delivery channel and linear transitions runner equates; This module can be split into the n fluid streams n+1 fluid streams (structures shown in Fig. 1-1-Fig. 1-5);
The micro-channel unit of described fluid diverter module B forms by converging mutually the linear fluid channel that the m sliver transvers section area be communicated in linear fluid channel port equates, the linear fluid channel of this m bar is dispersion shape and arranges; It is the fluid course entrance that the linear fluid channel of this m bar is converged communications ports mutually, and the other end of the linear fluid channel of this m bar is the fluid course outlet.The function of this module is that a fluid streams directly is split into m fluid streams (structures shown in Fig. 1-6);
The micro-channel unit that described fluid converges module is comprised of the n bar linearity delivery channel that the linear input duct of n+1 bar and a linear transitions runner by vertical placement with it are connected with the linear input duct of this n+1 bar, described n is the positive integer more than or equal to 1, the cross-sectional area of described linear input duct, linear delivery channel and linear transitions runner equates (be actually Fig. 1-1 to the linear input duct of module shown in Fig. 1-5 and change linear delivery channel into, linear delivery channel changes the module shown in linear input duct into); The function of this module is that the n+1 fluid streams is merged into the n fluid streams;
The micro-channel unit of described fluid variable resistance module forms by being the linear fluid channel that cross-sectional area that serpentine shape arranges equates, fluid course entrance on this linearity fluid channel, with 0-Y runner exit, the effect of this module is to change the flow resistance of this module by the length that changes the miniflow pipeline, and then is used for the flow behavior (modules Fig. 1-7 shown in) of fluid in the miniflow network;
Described fluid collection module has two kinds, a kind ofly be: the micro-channel unit of this fluid collection module is that the linear fluid channel of parallel arrangement becomes with the linear fluid channel that the both ends section tilts respectively laterally by s bar interlude, and the cross-sectional area of described linear fluid channel equates (modules shown in Fig. 1-8); Another kind is: the micro-channel unit of this fluid collection module forms by converging mutually the linear input duct that the t sliver transvers section area be communicated in a linear delivery channel equates, the cross-sectional area of this linear delivery channel is more than or equal to any linear input duct cross-sectional area (modules shown in Fig. 1-9);
The micro-channel unit of described fluid speed adjusting module is the linear fluid channel (modules shown in Fig. 1-10) that cross-sectional area is linear change.
Micro-channel unit module of the present invention is similar to some primary elements in circuit, can convection cell mobile in network regulate and control.Described micro-channel unit module can make up to design the flow behavior of fluid, thereby can realize specific function, as produces specific concentration gradient, and the resistance of measurement fluid etc.
Described combination is to realize as tygon (PE) plastic tube by the device that contains the small size pipeline.By PE pipe softness, that internal diameter is little, can easily modules be coupled together.
Described combination comprises:
1, a kind of micro-fluidic network system (as shown in Figure 3) that can be used for producing linear concentration gradient:
Described system forms with driving pump, diverter module, collection module and coupling arrangement;
This system can produce the linear gradient of any slope.
2, a kind ofly can be used for producing arbitrarily, the micro-fluidic network system (as shown in Figure 5) of real-time concentration gradient.
Described system forms with driving pump, diverter module, fluid variable resistance module, collection module and coupling arrangement.That this system can produce is real-time, concentration gradient arbitrarily.
3, a kind of micro-fluidic network system (as shown in Figure 9) that can be used for measuring the microfluid flow resistance.
Described system forms with driving pump, diverter module, fluid variable resistance module, flow resistance to be measured and coupling arrangement.This system can be used for measuring the flow resistance of micro-fluidic network easily.
The principle of the generation linear concentration gradient of described combination 1 is as follows: please refer to Fig. 3:
(one is original solution when two strands of liquid with same traffic, one is dilution) when entering the diverter module A of two entrances, three outlets, A has symmetrical structure due to diverter module, two fluid streams become the three identical fluids of plume amount and flow out from diverter module, and then enter the diverter module of the diverter module of three entrances, four outlets, become the 4 identical fluids of plume amount, the like.。。In the process of shunting, in each diverter module, fluids of other centres are all the results of two fluid streams proportionings with original liquid component is consistent except leftmost one and rightmost one, so different concentration is arranged.When the fluid with variable concentrations flows out from last diverter module, when entering collection module, namely formed concentration gradient in collection module.Because the diverter module that designs has symmetrical structure, thereby formation is linear concentration gradient.Although the formation principle of this gradient is at patent US7314070B2, US0129336A1, CN
Introduction is arranged in 101165161A etc., but above-mentioned what all adopt is integrated system, but not the modular structure of mentioning in the present invention.The method of application module not only can produce the concentration gradient the same with above-mentioned integrated system, and the diverter module of design is masterplate in advance, carries out a large amount of moulds that turns over.So just can greatly reduce the preparation time of concentration gradient device, reduce the dependence to little process equipment, and the module of damaging in the replacement module system at any time, the stable supply that keeps concentration gradient.
The generation of described combination 2 is any, the principle of real-time concentration gradient is as follows:
The diverter module B that two fluid streams (original solution and dilution) are introduced respectively.Diverter module has m outlet, and blocking does not according to actual needs need the outlet used, as using wherein X+1 outlet.Two diverter module B are divided into tributary, X+1 road with a fluid respectively.Directly being connected with collection module together in the tributary, X+1 road of original solution diverter module, directly being connected with collection module together in the tributary, X+1 road of dilution diverter module.
All the other X road in the tributary, X+1 road of dilution diverter module is connected with X entrance that converges module, and the entrance of only with one convergence device in any one tributary in X is connected;
All the other X road elder generations in the tributary, X+1 road of original solution diverter module and the entrance of X fluid variable resistance module, be connected with X entrance that converges module from the tributary, X road that X fluid variable resistance module flows out, another entrance of only with one convergence device in any one tributary in X is connected again;
X is converged module and plays a part original solution and dilution are mixed.Each converges module and only accepts from tributary of dilution diverter module with from a tributary of original solution dilution module.X converges module tributary, 2X road is mixed in twos after, flow out from outlet separately, obtain the X road with the solution of variable concentrations, the size of the concentration of per pass solution depends on the mixing ratio of converging module at this solution place, namely from the ratio of the size of the flow in original solution tributary that two entrances of module flow into and dilution tributary.The size of the flow in original solution tributary is to regulate by the fluid variable resistance module that is connected with the original solution diverter module.The solution of X road variable concentrations is linked among collection module, from together with 2 tributaries, road of dilution diverter module and original solution dilution module, has formed required concentration gradient with directly in collection module.Therefore, the size of the flow resistance value by setting X fluid variable resistance module just can obtain the solution of required different concentration, has also just obtained required concentration gradient.And, when real-time when regulating the flow resistance value of n module in X fluid variable resistance module, the concentration gradient in change collection module that just can be real-time.N is the positive integer less than or equal to x.
Determining by calculating of fluid variable resistance flow resistance of module value size.If there is no fluid variable resistance module, converge from each the liquid that module flows out so and have same concentrations.The calculating of the size of fluid variable resistance flow resistance of module value obtains according to fluid network and circuit analogy.In circuit, electric current is determined by the resistance sizes on each branch road in the distribution of each branch road; Equally, each flow resistance above fluid branch road is also determining the size (equation 1) of this flow above branch road, and fluid variable resistance module plays variable flow resistance just, is used for regulating the flow of the fluid above the branch road of place.The principle of fluid variable resistance module variable resistance is based on equation 2.According to equation 2 as can be known, in the situation that guarantee that miniflow pipeline cross-sectional area is constant, the size of flow resistance is directly proportional to the length L of pipeline, in the present invention, two the shortest interface distance of module supposition of design are 1 unit, then the distance between the interface of design is the integral multiple of bee-line, has therefore just obtained the quantification of interface distance.Thereby just can set or change by the length of setting pipeline the flow resistance value of variable resistance module.
ΔP＝QR (1)
Here P is the pressure of fluid, and Q is flow, and R is flow resistance, and m is the viscosity of fluid, h, and w, L are respectively the height of miniflow pipeline, width and length.
After the flow resistance value size of fluid variable resistance module is determined, the liquid that flows out from diverter module has different flows in different converging above module, thereby through converging the fluid that just produces variable concentrations after module (concentration is that the ratio according to the flow of original solution and dilution determines).Therefore, just can obtain the fluid of variable concentrations on collection module, i.e. a kind of concentration gradient.Conversely, known certain concentration gradient just can be extrapolated the size of fluid variable resistance module, because the size of fluid variable resistance module and concentration gradient are mutually to determine.Like this, just can come according to required concentration gradient arbitrarily the size of Fluid Computation variable resistance module, and connect among fluid network.This has just completed the structure that produces any concentration gradient micro fluidic device.
The principle of the micro-fluidic network system of the measurement microfluid flow resistance of described combination 3 is as follows:
According to patent US6575026B1, US6843121B1 and document [N.Srivastavaa and M.A.BurnsLab Chip, 2007,7,633-637] the principle of the measure of the change pressure that passes through gas volume, the present invention proposes the method for the pressure in a kind of modular measurement miniflow network.A kind of flow resistance measurer, it is characterized in that, converge module by driving pump, diverter module A, one, two fluid variable resistance modules and miniflow pipeline to be measured form diverter module 1 and directly are connected with driving pump, will tell two strands of liquid from the solution that driving pump flows out.One flow enters the entrance of miniflow pipeline to be measured, and flows out from the outlet of miniflow pipeline to be measured; Measured flow resistance value i.e. the size of the flow resistance from miniflow entrance to be measured to pipeline outlet.Another fluid streams is received the entrance of fluid variable resistance module.Because fluid variable resistance used herein only has an interface, thus fluid only can flow to fluid variable resistance module sinuous pipeline certain and stop, remaining part of pipeline of wriggling is the air that is closed.Because air contacts at the position that fluid stops with fluid, so the pressure of air equates with the pressure of fluid.And the size of the pressure of air can be according to its volume, and the volume that namely is closed in the ducted pipeline that wriggles calculates.
The fluid that flows out from pipe under test flows into an entrance that converges module, is another fluid variable resistance module with what converge that another entrance of module is connected.Fluid variable resistance module only has an interface with recited above the same.
Measure network according to flow resistance of the present invention, the pressure of the pressure of the porch of miniflow pipeline to be measured and the fluid variable resistance module that is connected with diverter module equates; The pressure in the exit of miniflow pipeline to be measured with equate with the pressure that converges the fluid variable resistance module that module is connected.The difference of the pressure of surveying of two fluid variable resistance modules is the pressure values of miniflow pipeline to be measured.Here the flow resistance of having ignored connecting tube.In fact, if the connecting tube that uses is very large with respect to miniflow pipeline cross-sectional area, its flow resistance can be similar to be ignored.
By the pressure of the miniflow pipeline that calculates, and the flow set of driving pump, both are divided by just can obtain required flow resistance value.It should be noted that the flow resistance value here is the account form definition that is analogous to the resistance in circuit, with respect to certain liquid (as temperature) and fix under certain conditions, different liquid has different flow resistance values.Utilize the method, can measure the flow resistance of the pipeline with labyrinth, as the pipeline of coarse structure is arranged on inwall.Such pipeline can not be used equation 2 and calculate flow resistance.
In the present invention, combination 1 can be applied to the Bu Tong screening of the condition of biology, chemical reaction with the concentration gradient that combination 2 produces, the gradient of the complexity in also can the mimic biology environment is come the concentration gradient response for cell, bacterium, virus, the oriented growth of neuron axon, the research of concentration gradient on impact of embryonic development etc.; Use speed adjusting module, can study cell, bacterium, the response of virus under different in flow rate stimulates, can combine with the response that concentration gradient stimulates; The flow resistance real-time monitoring devices of combination 3 designs can be measured easily and be difficult to the flow resistance value calculating to obtain by theory, thereby can better regulate and control fluid at the flow behavior of micro-fluidic pipeline.
Embodiment 1: the design of fluid variable resistance module:
As shown in Figure 2, the pipeline that is shaped as winding type of the pipeline of design.The width of pipeline is 100 microns, is highly 28 microns.At the end of pipeline, the turning, and connect and have on subterminal pipeline and the mark of being connected the interface that connects.According to formula (2), in the situation that the height of pipeline, width equate, its flow resistance is directly proportional to the length of pipeline.In Fig. 2, ho is 2 millimeters to the distance of h1, is made as unit length, and namely ho is 1 to the size of the flow resistance value between h1.H3 is 6 millimeters to the distance of ho, so its flow resistance value is 3.In like manner can get, ho is to h5, and ho is to h7, and he is to h2, and he is to h4, and he is respectively 5,7 to the flow resistance of h6, and 2,4,6.And any two the adjacent interfaces in middle part (as a and b) of the pipeline that wriggles is 14 millimeters apart from perseverance, so its flow resistance is 7.Like this, select ducted any two interfaces, just can obtain flow resistance value R=7*n+m, n is 0,1,2,3 positive integer, and m is 1,2,3,4,5,6.In fluid variable resistance module access miniflow network, just can regulate by the size of any its flow resistance of adjusting the size of flow of the fluid of its place miniflow network.
Embodiment 2: the generation of linear concentration gradient:
Select fluid diverter module (modules shown in Fig. 1-2 to Fig. 1-5), collection module (modules shown in Fig. 1-8 or Fig. 1-9) and driving pump in Fig. 1;
As shown in Figure 3, its structure is: the two-lines input duct entrance of first fluid diverter module is connected with described stoste driving pump and dilution driving pump respectively; Three linear delivery channel outlets of this first fluid diverter module are connected with three linear delivery channel entrances of second fluid diverter module respectively; By that analogy, 5 of the 4th fluid diverter module linear delivery channel outlets are connected with 4 linear fluid channel entrances respectively; 5 linear fluid channel outlets of the 4th fluid diverter module are connected with the linear fluid channel entrance of the fluid collection module shown in Fig. 1-8 or Fig. 1-9 respectively;
The uranin that needs is produced the 12mg/L of concentration gradient is drawn onto respectively in syringe as dilution as original solution and deionized water, syringe is placed in driving pump, and both flow velocity all is set as 1ml/h.
The diverter module of the different structure structure according to Fig. 3 is coupled together, and last pipeline out has 5.Can design again the module with more interfaces according to actual needs.
The pipeline that branches away is at last selected different collection modules according to actual needs.
Open the switch of driving pump, drive fluid flows in the miniflow network that builds.When the concentration of output reaches stable state, just can obtain needed linear concentration gradient.
That the observation of concentration gradient is used is inverted fluorescence microscope (Leica, DFC350FX), and excitation wavelength is 480nm; Experimental result as Fig. 4-1 to as shown in Fig. 4-4.Can find out, use this device can obtain linear good concentration gradient, and gradient can stable existence.Obtain more detailed concentration gradient, as long as the more diverter module of access.
The generation of any concentration gradient:
Select diverter module (modules shown in Fig. 1-6), the fluid variable resistance module (modules shown in Fig. 1-7) in Fig. 1 and receive
Collection module (modules shown in Fig. 1-8 or Fig. 1-9) and driving pump.
1, according to the method for attachment in Fig. 5, above-mentioned module is coupled together.What deserves to be explained is, restriction due to drawing, only provide 2 variable resistance modules (in fact can be designed to as required a plurality of), 2 situations (in fact can be designed to as required a plurality of) of converging module in Fig. 5, thereby can only produce 4 kinds of solution that concentration is different; If the example that provides uses 7 variable resistance modules and 7 to converge module, the variable resistance module is with the same shown in Fig. 5, under the diverter module on the right of all being connected on.
2, the uranin that needs is produced the 12mg/L of concentration gradient is drawn onto respectively in syringe as dilution as original solution and deionized water, syringe is placed in driving pump, and be 4ml/h with the flow set of original solution, dilution is set as 6ml/h.Suppose that 2mm is long, 100 microns wide, and the miniflow pipeline of 28 microns high is the flow resistance of a unit, regulates the flow resistance of each variable resistance module, makes their flow resistance be respectively: 27,8,2,13,38,66,84 unit flow resistances.
3, open driving pump, just can obtain concentration gradient as shown in Figure 6.Left one side of something of gradient is linear increment, and right one side of something is the curve of exponential damping.What Fig. 6 a and figure b used is different collection modules.This generating means with complicated concentration gradient is that other existing patent can't realize.
But the generation 1 of any concentration gradient of real-time change
1, directly regulate the size of the fluid variable resistance module in embodiment 3, just can obtain the variation of concentration gradient as shown in Figure 7.
2, adjacent fluorescence picture interval 2 minutes.After 18 minutes, obvious variation has occured in the pattern of the concentration gradient of output.(as shown in Figure 7) be linear increment by original left one side of something, right one side of something be the curve of exponential damping to become left one side of something be that para-curve increases progressively, right one side of something is the linear curve that successively decreases.The device of the concentration gradient of this exportable real-time change is that other existing patent can't realize.
But the generation 2 of any concentration gradient of real-time change
1, after in example 4 to be performed, the concentration gradient of output is stablized, obtain the gradient as shown in Fig. 8 a.
2, after the fluid (having 9) of change variable concentrations converges the module outflow from each, in the position of fluid collection module.The order on the fluid collection module of 1-9 bar pipeline is become [5 4321987 6] (as Fig. 8), just can obtain another concentration gradient as shown in Fig. 8 b.By such operation, can directly realize the variation of the output of concentration gradient, (Fig. 8 a), the speed of its realization is wanted obviously faster than the method shown in embodiment 4 although the variation here is based on original concentration gradient.
Embodiment 6
Measure in real time pressure and flow resistance in the miniflow network
1, select shunting in Fig. 1/converge module (module shown in Fig. 1-1), fluid variable resistance module (modules shown in Fig. 1-7) and flow resistance to be measured and driving pump and they are connected into a miniflow network.
2, fluid variable resistance module is an open outlet (as the point of the b in Fig. 9) only, and remaining is blocked.So just consisted of a system that reflects fluid pressure by the volume of air in the variable resistance module conduits.
3, open driving pump, as shown in Figure 9, more obvious greatly the time than miniflow pipeline when the cross-sectional area (being the pipeline of 400 microns as radius) of the connecting tube that uses, the reduction value of the pressure of the fluid that it is shared can be ignored.Therefore b point and c point have identical pressure, and d point and e point have identical pressure, and the pressure between c point and d point just is equal to pressure poor of two fluid variable resistance module Airs.The f point can access other miniflow networks, also can directly communicate with atmosphere.
4, flow and the above-mentioned equation 1 of the fluid that sets according to driving pump just can calculate c, the flow resistance value between d.
Claims (2)
1. fluid concentration gradient generator, it is characterized in that, this fluid concentration gradient generator is fluid any concentration gradient generator, this fluid concentration gradient generator converges module by an original solution driving pump, a dilution driving pump, 2 fluid diverter module B, X2 fluid variable resistance module, an X2 fluid and a fluid collection module forms, and X2 is the positive integer more than or equal to 2; Described fluid diverter module B, fluid variable resistance module, fluid converge module and the fluid collection module is all basic micro-channel unit modules, and described basic micro-channel unit module is comprised of element and the planar substrates that a surface has the micro-recesses unit; The surface with micro-recesses unit of described element and described planar substrates are bonded into one and consist of described basic micro-channel unit module; Described basic micro-channel unit module is used for being connected to each other to form by pipeline the micro-fluidic network system that has specific Fluid Flow in A behavior and realize specific function;
The micro-channel unit of described fluid diverter module B forms by converging mutually the linear fluid channel that the m sliver transvers section area be communicated in linear fluid channel port equates, the linear fluid channel of this m bar is dispersion shape and arranges; It is the fluid course entrance that the linear fluid channel of this m bar is converged communications ports mutually, and the other end of the linear fluid channel of this m bar is the fluid course outlet;
The micro-channel unit of described fluid variable resistance module forms by being the linear fluid channel that cross-sectional area that serpentine shape arranges equates, a fluid course entrance and a fluid course outlet are arranged on this linearity fluid channel;
The micro-channel unit that described fluid converges module forms by 2 input ducts with by a transition runner of vertical placement with it and 1 delivery channel that is connected with these 2 input ducts; The cross-sectional area of described input duct, linear delivery channel and transition runner equates;
The micro-channel unit of described fluid collection module is that s bar interlude is the linear fluid channel of parallel arrangement and the linear fluid channel composition that the both ends section tilts respectively laterally, and the cross-sectional area of described linear fluid channel equates; Perhaps
The linear input duct that the remittance mutually of serving as reasons is communicated in the t sliver transvers section area of a linear delivery channel forms, and the cross-sectional area of this linear delivery channel is more than or equal to any linear input duct cross-sectional area;
Described two fluid diverter module B are respectively original solution diverter module and dilution diverter module, the fluid course entrance of this original solution diverter module is connected with the original solution driving pump, and the fluid course entrance of dilution diverter module is connected with the dilution driving pump;
Described original solution diverter module and dilution diverter module have respectively a fluid course outlet to be connected with the linear input duct of described fluid collection module respectively;
All the other r-1 of described dilution diverter module fluid course outlets are connected with r-1 fluid input duct entrance that converges module, and any one fluid course outlet during this r-1 of described dilution diverter module fluid course exports only is connected with a fluid input duct entrance that converges module;
All the other r-1 of original solution diverter module fluid course outlets first are connected with the fluid course entrance of r-1 fluid variable resistance module, the fluid course outlet of this r-1 fluid variable resistance module is connected with r-1 fluid input duct entrance that converges module again, and any one fluid course outlet during this r-1 of described original solution diverter module fluid course exports only is connected with a fluid input duct entrance that converges module;
R-1 fluid delivery channel that converges module is connected with the input duct of fluid collection module respectively.
2. a flow resistance measurer, is characterized in that, converges module by an original solution driving pump, diverter module, one, and two fluid variable resistance modules and a miniflow pipeline to be measured form; Diverter module, converge module and fluid variable resistance module is all basic micro-channel unit modules, described basic micro-channel unit module is comprised of element and the planar substrates that a surface has the micro-recesses unit; The surface with micro-recesses unit of described element and described planar substrates are bonded into one and consist of described basic micro-channel unit module; Described basic micro-channel unit module is used for being connected to each other to form by pipeline the micro-fluidic network system that has specific Fluid Flow in A behavior and realize specific function;
The micro-channel unit of described diverter module forms by 1 linear input duct with by a linear transitions runner of vertical placement with it and 2 linear delivery channels that are connected with this 1 linear input duct; The cross-sectional area of described linear input duct and linear delivery channel equates;
The described micro-channel unit that converges module forms by 2 linear input ducts with by a linear transitions runner of vertical placement with it and 1 the linear delivery channel that is connected with these 2 linear input ducts; The cross-sectional area of described linear input duct and linear delivery channel equates;
The micro-channel unit of described fluid variable resistance module forms by being the linear fluid channel that cross-sectional area that serpentine shape arranges equates, this linearity fluid channel only has 1 fluid course entrance;
Described miniflow pipeline to be measured is by a linear fluid runner with a fluid course entrance and a fluid course outlet;
The fluid input duct of described diverter module is connected with the original solution driving pump, and 2 fluid delivery channels of this diverter module are connected with the runner entrance of a fluid variable resistance module and the fluid course entrance of miniflow pipeline to be measured respectively;
Described 2 fluid input ducts that converge module are connected with the fluid course outlet of miniflow pipeline to be measured and the runner entrance of another fluid variable resistance module respectively;
Fluid pressure in the fluid variable resistance module that the fluid pressure of the fluid course porch of miniflow pipeline to be measured equals to be connected with diverter module;
The fluid pressure in the fluid course exit of miniflow pipeline to be measured equal with converge the fluid variable resistance module that module is connected in fluid pressure;
Difference between fluid pressure in two fluid variable resistance modules is the fluid pressure reduction value in miniflow pipeline to be measured;
The ratio of the fluid delivery rate that the fluid pressure reduction value in miniflow pipeline to be measured and original solution driving pump are set is the flow resistance value of fluid.
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| CN103185802B (en) * | 2011-12-30 | 2016-03-02 | 北京纳迅科技股份有限公司 | Heterogeneous micro-fluidic Western blotting chip and its production and use |
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