CN101570776A - High-throughput nano-litre micro-droplet forming and fixing method based on microfluidic chip and special chip and application thereof - Google Patents
High-throughput nano-litre micro-droplet forming and fixing method based on microfluidic chip and special chip and application thereof Download PDFInfo
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- CN101570776A CN101570776A CN 200810011219 CN200810011219A CN101570776A CN 101570776 A CN101570776 A CN 101570776A CN 200810011219 CN200810011219 CN 200810011219 CN 200810011219 A CN200810011219 A CN 200810011219A CN 101570776 A CN101570776 A CN 101570776A
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Abstract
The invention relates to a high-throughput nano-litre micro-droplet forming and fixing method based on a microfluidic chip and a special chip and an application thereof. The method comprises the following steps: inlets of a continuous phase and a dispersed phase on the chip are respectively connected with two injection pumps through a teflon tube, the continuous phase and the dispersed phase are respectively infused into the chip under the driving action of the injection pumps, and continuous micro-droplets wrapped with single nematodes are formed in a T-shaped micro-droplet generation area; the generated micro-droplets enter in a droplet capture array and are captured in a circular droplet catcher in sequence; and after the micro-droplets are fully captured, the behaviors of the single nematodes in the droplet microenvironment are detected. The invention has the advantages that the microfluidic chip droplet technology is combined with the behavioral analysis to the single nematodes, a great amount of micro-droplets wrapped with the single nematodes are generated and fixed within the short time by using the characteristics of flexible combination and large-scale integration of various functional units on the chip, and the behavioral analysis to the high-throughput single nematodes on the microfluidic chip is realized for the first time.
Description
Technical field
The present invention relates to based on microfluidic chip liquid drop formation and fixing means and application thereof, a kind of high-throughput nano based on micro-fluidic chip upgrade little drop formation and fixing means, its special chip and the application in single nematode behavioural analysis are provided especially.
Background technology
Micro-fluidic chip (microfluidic chip) claims chip lab (lab on a chip) again, refer to integrated or be integrated into substantially on the chip of more than square centimeters (even littler) basic operation units such as specimen preparation related in the fields such as biological and chemical, reaction, separation, detections, form network by the microchannel, run through total system with controlled fluid, in order to replace a kind of technology of the breadboard various functions of conventional biological or chemical.Its essential characteristic and sharpest edges are that flexible combination and the scale of multiple monotechnics on small platform is integrated.Develop so far, the micro-fluidic chip technology has begun to be applied in the different field of life science, and has become one of important technological platform in the systems biology research.Recently, the microflow control technique based on drop has caused increasing concern.Compare with the microchannel, little drop has following advantage: size is littler, and flux is higher, and mass-and heat-transfer is rapider, transportation and fixing more flexible, and can form a relatively stable controlled drop microenvironment; Therefore, in many high throughput analysis in chemistry and biology field, little drop is used to the screening (as albumen crystallization, DNA analysis etc.) of reaction conditions as reactor, perhaps is used for wrapping up various particles (comprising cell, bacterium etc.) to carry out various biological studies.
For drop is monitored and analyzed, must at first carry out drop and fix.Present drop fixed form is divided into two kinds substantially: utilize dielectric power to fix or utilize in the passage surface properties of different zones to fix.Wherein, dielectric power is fixing easily to cause damage to the organism in the drop, and it is comparatively harsh to utilize hydrophilic and hydrophobic matter to fix the requirement of chip manufacturing, and the two all has certain limitation.The drop fixing means that the present invention relates to is that the combined effect that utilizes different size and the resistance to flow variation in the different moment passages by the microchannel to be produced is fixed drop, the micro-fluidic chip manufacturing that relates to is simple, convenient experimental operation, and the organism in the drop do not produced damage.
Although there has been the little drop of a lot of research and utilizations to carry out the high-throughput bioanalysis now, yet they also do not relate to the research to complex biological body (as the model animals nematode).Distinctive micro-dimension feature of little drop and nematode size are complementary, the integrated feature of chip flexible design and scale in addition, and being fit to the nematode very much is that object carries out the research of high-throughput idiobiology.
Caenorhabditis elegans (Caenorhabditis elegans) is a kind of model animals of classics, and it is widely used in fields such as growth, genetics, neurobiology and pharmacy.The nematode entire body is transparent, and growth cycle short (3 days), volume little (adult only 1mm is long, and about 50um is wide) is first multicellular organism of finishing genome sequencing.Existing known nematode gene group is equivalent to 1/30 of people's gene group approximately, its neural system has only 302 cells (accounting for somatocyte 1/3), but contain most of genes of coding vertebrate brain molecule, nearly all important mankind grow and disease gene all exists orthologous gene and coherent signal path to guard in nematode.Fact proved, the numerous disease phenotype energy faithful reappearance human disease processes of nematode, these specific characteristics make nematode become one of optimal mode organism of research human diseases.Such as in the research to nerve retrograde affection (as Parkinson's disease), nematode is exactly one of important models of carrying out the medicine screening.
At present, mostly adopt array microwell plate form, be about to culture of nematodes, be aided with the sample adding device of automatization and digital imaging system experimentize operation and information acquisition in 96 orifice plates based on the high-flux medicaments sifting of model animals nematode.Although automated operation is accelerated analysis speed, but still has many limitation: handle as micro-example automatic operating equipment tolerance range is had relatively high expectations; The small volume solution of open environment easily evaporates; The pre-treatment of sample (comprise culture of nematodes, medicine apply, solution washing etc.) process is still off-line carries out, and causes analytic process lengthy and tedious, and flux is low; The bulkiness of plant and instrument and expensive price make it to be difficult to be generalizable or the like.Generally speaking, the development of current model animals technology far can not be satisfied the needs of modern biological medicine research and development, therefore, exploitation is based on the new platform of high-flux medicaments sifting of model animals, realizes that the microminiaturization of triage techniques, integrated and with low costization are the inexorable trends of future development.The said microfluidic chip liquid drop technology in front is that the ideal that realizes the integral level high-flux medicaments sifting is selected just.
Summary of the invention
The purpose of this invention is to provide a kind of high-throughput nano upgrade little drop formation and fixing means, its special chip and application based on micro-fluidic chip.
The invention provides upgrade little drop of a kind of high-throughput nano and form and fixing means based on micro-fluidic chip,
Procedure is:
External phase on the chip is connected with two syringe pumps respectively by teflon pipe with the disperse phase inlet, under syringe pump drives, external phase and disperse phase are injected chip respectively, generate the district at the little drop of T type afterwards and form little drop that successive is enclosed with single nematode;
The little drop that produces continues to flow and enter the droplet capture array under syringe pump drives continuously, the mobile meeting of drop in passage causes the variation of resistance to flow in the passage, and along the conversion of the magnitude relationship of different paths circulating resistance, make drop select to enter specific path, thereby sequentially be trapped in the circular drop catcher at crotch;
After the little drop that is enclosed with the single line worm that produces is caught fully, close syringe pump and produce and fluid flow, micro-fluidic chip is placed under the stereoscopic microscope, the behavior of single nematode in the drop microenvironment detected to stop drop.
Upgrade little drop of high-throughput nano based on micro-fluidic chip provided by the invention forms and fixing means, and described external phase is oil phase, and disperse phase is a water; Preferred external phase is n-Hexadecane, and disperse phase is the nematode suspension.
The invention provides a kind of high-throughput nano that is specifically designed to and upgrade that little drop forms and the micro-fluidic chip of fixing means, this chip is made of two functional areas: the little drop of T type generates to be distinguished and the droplet capture array that contains 180 identical structural units; Two sample introduction ends that the little drop of T type generates the district are respectively external phase and disperse phase inlet, and each structural unit in the droplet capture array contains the drop catcher of a circle, between each drop catcher by successive square waveform channel connection.
The invention provides be used for that high-throughput nano upgrades that little drop forms and the micro-fluidic chip of fixing means in the application of single nematode behavioural analysis.
Little drop of the single nematode of parcel provided by the invention forms principle: the intersection that generates the district at the little drop of T type, under shearing force and surface tension effects, the nematode suspension of suitable density is cut into the continuous little drop that is enclosed with single nematode by external phase (n-Hexadecane).
Little droplet capture principle provided by the invention is: the little drop that generates district's generation at the little drop of T type continues to flow and enter the droplet capture array under syringe pump drives, the mobile meeting of little drop in passage causes the variation of resistance to flow in the passage, and along the conversion of the magnitude relationship of different paths circulating resistance, make little drop select to enter the less path of specific flow resistance, thereby sequentially be trapped in circular little drop catcher at crotch.
The present invention has following advantage:
1. the present invention only need add continuous little drop that nematode suspension and n-Hexadecane just can generate the single nematode of parcel automatically in passage intersection to two inlets in the little drop generation of T type district respectively;
2. little drop of the present invention's generation can enter the droplet capture array automatically and sequentially is trapped in circular little drop catcher under syringe pump drives;
3. creativeness of the present invention is integrated multiple drop operation on chip, comprises generations, transportation and fixes etc., and be research object with the model animals nematode, and the motor behavior of the single nematode of high-throughput is analyzed;
4. compare with traditional porous plate technology, the present invention has simplified sorting and has shifted the operating process of single nematode, has reduced the consumption of nematode and reagent significantly, has shortened experimental period;
5. the present invention creatively combines the microfluidic chip liquid drop technology with single nematode behavioural analysis, utilize various functional unit flexible combination on the chip, the integrated feature of scale, produce at short notice and the fixing little drop that is enclosed with single nematode in a large number, realized on micro-fluidic chip behavioural analysis first the single nematode of high-throughput.
Description of drawings
Fig. 1 integrated micro-flow control chip platform: (a) be chip one-piece construction synoptic diagram, wherein, 1 is that the little drop of T type generates the district, and 2 is the droplet capture array, and 3 are the external phase inlet, and 4 are the disperse phase inlet, and 5 is waste liquid outlet; (b) be the enlarged view of a structural unit in the droplet capture array;
The little drop of Fig. 2 T type generates drop forming process synoptic diagram in the district, and wherein, 1 is water, and 2 is oil phase;
The fixation procedure synoptic diagram of the little drop of Fig. 3 in capture array, wherein, 1 is step 1: drop 1 is positioned at the crotch in path 1 and path 2, and the fluid resistance in path 1 is greater than the fluid resistance in path 2 at this moment; 2 is step 2: drop 1 is 2 inflow square waveform passages along the path, and drop 2 is positioned at the crotch in path 1 and path 2, and the fluid resistance in path 1 is less than the fluid resistance in path 2 at this moment; 3 for step 3: drop 21 enters drop catcher and is fixed along the path, and drop 3 is positioned at the crotch in path 1 and path 2, this moment path 1 fluid resistance greater than the fluid resistance in path 2;
Fig. 4 (a) is the forming process of the little drop of ink on this micro-fluidic chip; (b) be the Photomicrograph of little drop after fixing;
Fig. 5 (a) is the forming process of little drop of the single nematode of parcel on this micro-fluidic chip; (b) be the Photomicrograph of little drop after fixing;
The Photomicrograph of the little drop of the single nematode of the parcel that Fig. 6 is fixed: (a) be four little drop photos of successive; (b) different motion shape that the nematode that is wrapped in little drop presents after 70 minutes in 3mM MPP+ effect: I is a C shape, and II is a sinusoidal, and III is a Ω shape, and IV is stiff shape;
Fig. 7 impassivity toxin MPP+ effect down, the hunting frequency of 6 single nematodes and action time graph of a relation;
Fig. 8 impassivity toxin MPP+ effect down, the average hunting frequency of 6 nematodes and action time graph of a relation;
Fig. 9 impassivity toxin MPP+ effect down, the Ω shape of 6 single nematodes motion in swing per-cent and action time graph of a relation;
Figure 10 impassivity toxin MPP+ effect down, the Ω shape of 6 nematodes motion in swing average percent and action time graph of a relation;
Figure 11 concentration be 3mM neurotoxin MPP+ effect down, the hunting frequency of 6 single nematodes and action time graph of a relation;
Figure 12 concentration be 3mM neurotoxin MPP+ effect down, the average hunting frequency of 6 nematodes and action time graph of a relation;
Figure 13 concentration be 3mM neurotoxin MPP+ effect down, the Ω shape of 6 single nematodes motion in swing per-cent and action time graph of a relation;
Figure 14 concentration be 3mM neurotoxin MPP+ effect down, the Ω shape of 6 nematodes motion in swing average percent and action time graph of a relation;
Figure 15 concentration be 5mM neurotoxin MPP+ effect down, the hunting frequency of 6 single nematodes and action time graph of a relation;
Figure 16 concentration be 5mM neurotoxin MPP+ effect down, the average hunting frequency of 6 nematodes and action time graph of a relation;
Figure 17 concentration be 5mM neurotoxin MPP+ effect down, the Ω shape of 6 single nematodes motion in swing per-cent and action time graph of a relation;
Figure 18 concentration be 5mM neurotoxin MPP+ effect down, the Ω shape of 6 nematodes motion in swing average percent and action time graph of a relation.
Embodiment
The following examples will give further instruction to the present invention, but not thereby limiting the invention.
External phase on the micro-fluidic chip shown in Figure 1 is connected with two syringe pumps respectively by teflon pipe with the disperse phase inlet, under syringe pump drives, n-Hexadecane and green ink are injected chip respectively, generate district's green little drop of formation successive at the little drop of T type and (see Fig. 4 a); Little drop continues to flow into the droplet capture array under syringe pump drives, and sequentially is trapped in the circular drop catcher (seeing Fig. 4 b); Close down syringe pump at last and produce and fluid flow to stop drop, 180 of the homogeneous that obtains being fixed receive the little drop of upgrading.
External phase on the micro-fluidic chip shown in Figure 1 is connected with two syringe pumps respectively by teflon pipe with the disperse phase inlet, under syringe pump drives, n-Hexadecane and nematode suspension are injected chip respectively, and the little drop that is enclosed with single nematode at the little drop generation of T type district's formation successive (is seen Fig. 5 a); Little drop continues to flow under syringe pump drives, and enters the droplet capture array and sequentially be trapped in the circular drop catcher (to see Fig. 5 b, 6a); Close down syringe pump and produce and fluid flow, micro-fluidic chip is placed under the stereoscopic microscope, analyze the motor behavior of single nematode under the drop microenvironment and (see Fig. 7-Figure 10) to stop drop.Can find from the result, in detection time (2 hours), the motion of nematode keeps higher hunting frequency (about 2.6) in the drop, and the frequency lower (being about 1%) that Ω form (a kind of dyskinesia form) occurs, the motor behavior of proof nematode is normal, and this method is to the not obviously influence of motor behavior of nematode.
External phase on the micro-fluidic chip shown in Figure 1 is connected with two syringe pumps respectively by teflon pipe with the disperse phase inlet, under syringe pump drives, n-Hexadecane and the nematode suspension that contains finite concentration neurotoxin MPP+ (3mM, 5mM) are injected chip respectively, and the little drop that is enclosed with single nematode at the little drop generation of T type district's formation successive (is seen Fig. 5 a); Little drop continues to flow under syringe pump drives, and enters the droplet capture array and sequentially be trapped in the circular drop catcher (to see Fig. 5 b, 6a); Close down syringe pump and produce and fluid flow, micro-fluidic chip is placed under the stereoscopic microscope, detect the variation of the motor behavior (hunting frequency, the Ω form frequency of occurrences) of single nematode under different concns neurotoxin MPP+ effect to stop drop.Fig. 7-Figure 18 has shown that the neurotoxin MPP+ of different concns induces down, motor behavior of nematode (hunting frequency, the Ω form frequency of occurrences) and graph of a relation action time.Wherein, Fig. 7,11,15 and Fig. 8,12,16 be respectively hunting frequency and the mean value thereof of single nematode under the MPP+ of blank, 3mM, 5mM effect, Fig. 9,13,17 and Figure 10,14,18 be respectively the Ω form frequency of occurrences and the mean value thereof of single nematode under the MPP+ of blank, 3mM, 5mM effect.By among Fig. 7-Figure 10 as can be seen, no MPP+ does the time spent, the control group nematode was kept the higher hunting frequency (being about 2.6) and the lower Ω form frequency of occurrences (being about 1%) in 2 hours; By among Figure 11-Figure 14 as can be seen, under 3mM MPP+ effect, the hunting frequency of nematode occur to descend (reducing to 1.3 from 2.7) at 90-120 minute, the Ω form frequency of occurrences rises to 13% by 5% simultaneously; By among Figure 15-Figure 18 as can be seen, under 5mM MPP+ effect, the hunting frequency of nematode remains on lower (being about 1.1), and the Ω form frequency of occurrences presents than great fluctuation process (0-100%).Above data show that under the effect of MPP+, obstacle (hunting frequency reduces, and the Ω form frequency of occurrences raises) appears in the motor behavior of nematode, and increases along with the increase of MPP+ concentration.
Claims (5)
1, upgrade little drop of a kind of high-throughput nano based on micro-fluidic chip forms and fixing means, it is characterized in that:
Procedure is:
External phase on the chip is connected with two syringe pumps respectively by teflon pipe with the disperse phase inlet, under syringe pump drives, external phase and disperse phase are injected chip respectively, generate the district at the little drop of T type afterwards and form little drop that successive is enclosed with single nematode;
The little drop that produces continues to flow and enter the droplet capture array under syringe pump drives continuously, makes drop select to enter the less path of specific flow resistance at crotch, thereby sequentially is trapped in the circular drop catcher.
2, form and fixing means according to upgrade little drop of the described high-throughput nano based on micro-fluidic chip of claim 1, it is characterized in that: described external phase is oil phase, and disperse phase is a water.
3, form and fixing means according to upgrade little drop of the described high-throughput nano based on micro-fluidic chip of claim 2, it is characterized in that: described external phase is n-Hexadecane, and disperse phase is the nematode suspension.
4, a kind of claim 1,2 or 3 described high-throughput nanos of being specifically designed to upgrades that little drop forms and the micro-fluidic chip of fixing means, and it is characterized in that: this chip is made of two functional areas: the little drop of T type generates district and the droplet capture array that contains 180 identical structural units; Two sample introduction ends that the little drop of T type generates the district are respectively external phase and disperse phase inlet, and each structural unit in the droplet capture array contains the drop catcher of a circle, between each drop catcher by successive square waveform channel connection.
5, claim 4 described be used for that high-throughput nano upgrades that little drop forms and the micro-fluidic chip of fixing means in the application of single nematode behavioural analysis.
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