CN101464458B - Micro-flow controlled chip used for detecting erythrocyte osmotic fragility - Google Patents
Micro-flow controlled chip used for detecting erythrocyte osmotic fragility Download PDFInfo
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- CN101464458B CN101464458B CN 200810218355 CN200810218355A CN101464458B CN 101464458 B CN101464458 B CN 101464458B CN 200810218355 CN200810218355 CN 200810218355 CN 200810218355 A CN200810218355 A CN 200810218355A CN 101464458 B CN101464458 B CN 101464458B
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Abstract
The invention relates to a micro-fluidic chip used for testing erythrocyte osmotic fragility, which comprises a chip main-body, wherein, two solution inlets and a blood sample inlet are formed on the chip main-body; and a plurality of detection pools arranged inside the chip main-body are communicated with the blood sample inlet through a blood sample microchannel and communicated with the two solution inlets through a microchannel network that generates concentration gradient automatically. Based on the micro-fluidic chip, a test method of erythrocyte osmotic fragility comprises the steps asfollows: (1) blood samples are introduced into the different detection pools in the micro-fluidic chip through the blood sample inlet; (2) two NaCl solutions with different concentrations are introduced into the micro-fluidic chip through the two solution inlets at the same flow speed at the same time, and mixed with the blood samples in the detection pools; (3) erythrocytes in the detection pools are observed through a microscope and are shoot; and (4) the intact erythrocytes in each detection pool are distinguished in erythrocyte pictures and counted. The micro-fluidic chip reduces use of blood, reduces manual intervention, and has high detection speed and objective and accurate detection results.
Description
Technical field
The present invention relates to the osmotic fragility inspection technology, particularly a kind of micro-fluidic chip that can automatically generate concentration gradient and based on the osmotic fragility method of inspection of micro-fluidic chip.
Background technology
Haemolysis appears in red blood cell in hypotonic salt solusion characteristic is called osmotic fragility, is an important clinical hematology test rating.Endoerythrocytic osmotic pressure and plasma osmolarity place isotonic solution (0.9%NaCl) with red blood cell about equally under the normal condition, can keep normal size and form; If red blood cell is placed hypertonic solution (＞0.9%), moisture can be overflowed outside the born of the same parents, and cell is because of the dehydration shrinkage; If red blood cell is placed hypotonic solution (＜0.9%), moisture enters cell, and red blood cell expands and becomes sphere, and inflatable to breaking, haemoglobin is discharged in the solution, is called haemolysis.Normocyte generally begins to occur haemolysis in 0.42%NaCl solution, and complete hemolysis in 0.35%NaCl solution, so represent normocytic osmotic fragility scope with the NaCl solution of 0.42-0.35%.Osmotic fragility increases, common hereditary spherocytosis; Osmotic fragility reduces, common thalassemia, hypoferric anemia etc.Conventional checked operation method needs the NaCl solution of 12 variable concentrations of artificial preparation, does contrast test with normal person's blood sample and patient's blood sample, leaves standstill after 2 hours and obtains assay by naked-eye observation, and complicated operation, manual intervention are large.
Summary of the invention
The purpose of this invention is to provide a kind of osmotic fragility method of inspection that can realize quick test, reduce blood using amount and minimizing manual intervention, and the micro-fluidic chip that is used for this method of inspection.
Micro-fluidic chip is a Biochemical Lab that makes up at more than one square centimeters chip, it is take MEMS (Micro Electro Mechanical systems) processing technology as the basis, at silicon chip, make the microchannel on the material such as glass or PDMS, and form network by the microchannel, run through whole system with controlled fluid, realize related reaction in the biological and chemical field, separate, check, the basic operations such as cell cultivation, in order to replace the various functions in conventional biological or chemical laboratory, therefore be also referred to as " Laboratory on chip microarray (Lab-on-a-chip) ".Have obvious microminiaturization, the characteristics such as integrated and portable.Compare with the common method in present laboratory, use micro-fluidic chip cell to be operated and analyzes main advantage and be: 1) microchannel size and cell size are complementary, greatly about 10-100 μ m; 2) micro-fluidic chip provides the space of a relative closure, reduces external environment to the stimulation of cell; 3) can directly examine under a microscope the operation on micro-fluidic chip, cell carried out and the situation of cell; 4) the micro-fluidic chip volume is small, has saved the consumption of cell solution and other reagent, and the microchannel heat and mass is rapid, and the reaction time also greatly reduces; 5) operation of several steps such as cell sample, separation, analysis can be integrated in the chip piece last time finishes.
The concrete technical scheme of the present invention is as follows: a kind of osmotic fragility method of inspection based on micro-fluidic chip may further comprise the steps:
A, with micro-injection pump with in the different detection cells in the blood sample import input micro-fluidic chip of blood sample by micro-fluidic chip;
B, with micro-injection pump with the NaCl solution of two kinds of variable concentrations with identical flow velocity simultaneously in two solution inlet port input micro-fluidic chips of described micro-fluidic chip, make the NaCl solution of variable concentrations by the microchannel network of the automatic generation concentration gradient in the micro-fluidic chip, and send into respectively in the different detection cells, mix with blood sample in the detection cell;
C, with microscopic examination and take red blood cell photo in each detection cell;
D, from the red blood cell photo identification each detection cell in complete red blood cell and the counting.
In step b, in the NaCl solution of two kinds of variable concentrations that add, wherein a kind of concentration of NaCl solution is 0%～0.25%, and the concentration of another kind of NaCl solution is 0.5%～0.9%.
In steps d, preferred version is, identify complete red blood cell and counting in each detection cell by computing machine with image processing method, specifically may further comprise the steps: with threshold method the photo of microscope photographing is divided into red blood cell and non-red blood cell zone first, again with area-method statistics red blood cell number and calculating cell size.In the situation that does not have the Computer Image Processing condition, also can go out macroscopic RBC number in the red blood cell photo by people's number.
Wherein, micro-fluidic chip comprises chip body, two solution inlet port and a blood sample import are set on the chip body, some detection cells are set in the chip body, described some detection cells are rods arranged in horizontal line, they are communicated with the blood sample import by the blood sample microchannel, and are communicated with two solution inlet port by the microchannel network that automatically generates concentration gradient; The microchannel network of described automatic generation concentration gradient comprises some groups of hybrid channels that are arranged in parallel, organize to last from first group, the quantity of the hybrid channel that comprises increases progressively successively, the entrance of all hybrid channels in every group, and the outlet of all hybrid channels all is connected on the overall channel in upper one group, arrange in a triangle two hybrid channels adjacent with this hybrid channel in each hybrid channel and next group, and the overall channel equal in length in the outlet of each hybrid channel and next group between the entrance of two hybrid channels adjacent with this hybrid channel, the outlet correspondence of each hybrid channel is linked described some detection cells in last group, the overall channel of first group of hybrid channel is communicated with described two solution inlet port in two diverse locations, and solution inlet port equates with passage length between the entrance of the first two hybrid channel in first group, and another solution inlet port equates with passage length between the entrance of latter two hybrid channel in first group.
Described hybrid channel is serpentine channel, and its shape can be S shape or zigzag or bow font etc., and its function is that two kinds of solution that flow in it are fully mixed.The hybrid channel can be designed to the cross section and be the passage of the shapes such as circle, rectangle, square or triangle, and the passage internal diameter is 20～100 microns, and the degree of depth of detection cell is 20～100 microns.Preferred 30～60 microns of the detection cell degree of depth.
A kind of micro-fluidic chip for the check osmotic fragility, comprise chip body, it is characterized in that: two solution inlet port and a blood sample import are set on the described chip body, some detection cells are set in the chip body, described some detection cells are rods arranged in horizontal line, the degree of depth of detection cell is 30～60 microns, and they are communicated with the blood sample import by the blood sample microchannel, and is communicated with two solution inlet port by the microchannel network that automatically generates concentration gradient; The microchannel network of described automatic generation concentration gradient comprises some groups of hybrid channels that are arranged in parallel, organize to last from first group, the quantity of the hybrid channel that comprises increases progressively successively, the entrance of all hybrid channels in every group, and the outlet of all hybrid channels all is connected on the overall channel in upper one group, arrange in a triangle two hybrid channels adjacent with this hybrid channel in each hybrid channel and next group, and the overall channel equal in length in the outlet of each hybrid channel and next group between the entrance of two hybrid channels adjacent with this hybrid channel, the outlet correspondence of each hybrid channel is linked described some detection cells in last group, first group comprises three hybrid channels, the overall channel of first group of hybrid channel is communicated with described two solution inlet port in two diverse locations, and solution inlet port equates with passage length between the entrance of the first two hybrid channel in first group, and another solution inlet port equates with passage length between the entrance of latter two hybrid channel in first group.
The present invention by micro-fluidic chip automatic preparation concentration gradient NaCl solution and automatic subpackaging in different detection cells, mix with the blood sample in the detection cell, take pictures with microscope, then realize the check of osmotic fragility by computing machine with image processing method statistics intact cell number.Its whole solution preparation process is all finished automatically in micro-fluidic chip inside, does not need artificial preparation, has reduced manual intervention, has shortened detection time widely, has reduced simultaneously the stimulation of external environment to cell, has improved the accuracy that detects.And the blood sample of its use can reduce to micro updating, has greatly reduced blood using amount.
Because it utilizes microscope to take pictures, then add up the intact cell number by computing machine with image processing method, further reduced manual intervention, make testing result more objective, accurate, and make detection speed faster.
Description of drawings
Fig. 1,2 is respectively external structure synoptic diagram and the schematic internal view of micro-fluidic chip among the present invention;
Fig. 3 is the structural representation of the inner microchannel of its micro-fluidic chip network.
Embodiment
The present invention transfers to the related check of erythrocyte fragility on the micro-fluidic chip and carries out, can on chip, go out concentration gradient by automatic preparation, red blood cell is sent in the detection cell of each variable concentrations, examined under a microscope change of red blood cell, and with image processing method red blood cell is identified.The dividing method of intensity-based threshold value is a kind of image partition method of classics, and it presses the some classes of gray scale fraction to pixel by threshold value is set, thereby realizes image segmentation.For our erythrogram, only need be divided into cell and the acellular district gets final product, then add up the area of cell, intact cell is counted.Be described further below in conjunction with accompanying drawing.
This may further comprise the steps based on the osmotic fragility method of inspection of micro-fluidic chip:
A, with micro-injection pump with in the different detection cells in the blood sample import input micro-fluidic chip of blood sample by micro-fluidic chip;
B, with micro-injection pump with the NaCl solution of two kinds of variable concentrations with identical flow velocity simultaneously in two solution inlet port input micro-fluidic chips of described micro-fluidic chip, make the NaCl solution of variable concentrations by the microchannel network of the automatic generation concentration gradient in the micro-fluidic chip, and send into respectively in the different detection cells, mix with blood sample in the detection cell;
C, with microscopic examination and take red blood cell photo in each detection cell;
D, process described red blood cell photo by computing machine with image processing method, identify complete red blood cell and counting in each detection cell.Also can go out macroscopic RBC number in the red blood cell photo by people's number.
In step b, in the NaCl solution of two kinds of variable concentrations that add, a kind of concentration of NaCl solution is 0%～0.25%, and the concentration of another kind of NaCl solution is 0.5%～0.9%.There is a kind of concentration of solution to be 0 in two kinds of solution, that is to say, can add NaCl solution from a solution inlet port, add pure water from another solution inlet port.And the adding mode can be to use a double-channel trace syringe pump (such as the KDS 200 of U.S. KDScience company), also can use two single channel micro-injection pumps (such as the KDS 100 of U.S. KDScience company), can also use two passages of a hyperchannel micro-injection pump, but no matter which kind of mode of employing, must guarantee to add to two solution inlet port simultaneously, and the flow velocity of two solution inlet port is identical, and flow velocity generally is set in the order of magnitude of 0.1 μ l/min.
In steps d, the image processing method that adopts comprises: with threshold method the photo of microscope photographing is divided into red blood cell and non-red blood cell zone first, adds up complete red blood cell number and calculate cell size with area-method again.
With reference to Fig. 1-3, micro-fluidic chip comprises the chip body that is made of upper substrate 1 and subtegulum 2 in the present embodiment, two solution inlet port 3,4 and blood sample imports 5 are set on the chip body, eight detection cells 61～68 are set in the chip body, described eight detection cells 61～68 are rods arranged in horizontal line and form detection cell group 6, they are communicated with blood sample import 5 by blood sample microchannel 10, and are communicated with two solution inlet port 3,4 by the microchannel network 7 that automatically generates concentration gradient; The microchannel network 7 of described automatic generation concentration gradient comprises six groups of S shape serpentine channel 71～76 that are arranged in parallel, first group of S shape serpentine channel 71 contains three S shape serpentine channel 712,713,714, from first group 71 to last group 76, the quantity of the S shape serpentine channel that comprises increases progressively successively, the 6th group of S shape serpentine channel 76 contains eight S shape serpentine channel 762～769, the entrance of all S shape serpentine channel in every group, and the outlet of all S shape serpentine channel all is connected on the overall channel in upper one group, as: in the 6th group in the entrance of all S shape serpentine channel 762～769 and the 5th group the outlet of all S shape serpentine channel all be connected on the overall channel 761, two the S shape serpentine channel adjacent with this S shape serpentine channel are arranged in a triangle in each S shape serpentine channel and next group, such as wriggle S shape serpentine channel 722 in logical 712 and second groups of: the S shape in first group, 723 arrange in a triangle, S shape in the 5th group S shape serpentine channel 762 in logical 752 and the 6th groups of wriggling, 763 arrange in a triangle, and the passage length in the outlet of each S shape serpentine channel and next group between the entrance of two S shape serpentine channel adjacent with this S shape serpentine channel equates, such as wriggle S shape serpentine channel 722 in logical 712 outlet and second group of: the S shape in first group, passage length between 723 the entrance equates, to guarantee flowing into S shape serpentine channel 722 from S shape sinuous logical 712,723 solution equates; The outlet correspondence of each S shape serpentine channel 762～769 is linked described eight detection cells 61～68 in last group, the overall channel 711 of first group of S shape serpentine channel 71 passes through respectively two passages 8 in two diverse locations, 9 are connected to described two solution inlet port 3,4, more particularly, solution inlet port 3 is connected in first group of S shape serpentine channel 71 on the overall channel 711 between the first two S shape serpentine channel 712 and 713 by passage 8, and the passage length between the entrance of solution inlet port 3 and two S shape serpentine channel 712 and 713 equates, solution inlet port 4 is connected in first group of S shape serpentine channel 71 on the overall channel 711 between latter two S shape serpentine channel 713 and 714 by passage 9, and the passage length between the entrance of solution inlet port 4 and two S shape serpentine channel 713 and 714 equates.
Micro-fluidic chip can also be designed to have detection cell still less among the present invention, perhaps has more detection cell, and correspondingly, the group number that automatically generates the S shape serpentine channel that the microchannel network 7 of concentration gradient comprises also can change.
Described each passage (comprising S shape serpentine channel) can be designed to the cross section and be the passage of the shapes such as circle, rectangle, square or triangle, and the passage internal diameter is 20～100 microns, and the degree of depth of detection cell 61～68 can be designed to 20～100 microns.The degree of depth of detection cell is preferably designed for 30～60 microns.
In the present embodiment, each detection cell also equates to equal in length, the internal diameter of the passage between the blood sample import 5.
Micro-fluidic chip is to be made by the substrate 1 of two printing opacities, 2 involutions, form the micro-groove that consists of described detection cell and each passage on one of them substrate 1, another substrate 2 is close to opening one side of described micro-groove, behind two substrate involutions the open side of described micro-groove is sealed the described microchannel of formation and detection cell.Wherein, substrate 1,2 can adopt PDMS, glass or other macromolecular material to make.
Micro-fluidic chip also can be made by a PDMS substrate and a glass sheet bonding, and wherein the PDMS substrate is made by the microchannel mould, and the microchannel mould adopts the MEMS processing technology to make.A kind of concrete manufacturing process is as follows:
1. use the design configuration of computerized mapping Software on Drawing micro-fluidic chip, as shown in Figure 3;
2. making lay photoetching mask plate
Mask material can be selected 5 inches chromium plating glass plates, and electron beam exposure is transferred to design configuration on the mask.
3. exposure, development
Clean 4 cun silicon chips, its surface uniform be coated with last layer photoresist (positive glue), expose by the transparent part in the mask that is painted with predetermined pattern at light beam with the silicon chip of photoresist, then pattern part has been protected by photoresist.
4. plasma etching (ICP)
High-energy plasma body striking silicon slice with air inclusion molecule, free electron and gaseous ion is surperficial, and removes silicon from the surface, and so far, the microchannel mould is made complete.
5. make the PDMS substrate
PDMS mixes according to mass ratio with hardening agent at 10: 1, stir, remove bubble, be poured on the mould of microchannel, place baking oven to solidify about 1 hour rear the taking-up with 70 degree, cool off, take the PDMS of shaping off, punch with boring cutter at passage blood sample injection port and solution inlet port, namely make the PDMS substrate.
6. encapsulation
The PDMS substrate sticks together with glass sheet after the oxygen gas plasma surface treatment.
Utilize micro-fluidic chip among the present invention can automatically generate the NaCl solution of concentration gradient, and can determine the concrete concentration of NaCl solution in each detection cell, the following describes its principle: with reference to Fig. 3, being provided with concentration and being A and B volume is two kinds of NaCl solution of 1 and enters micro-fluidic chip from two solution inlet port 3,4 respectively, in the shunting of the point of crossing of microchannel, mix with diffusion way in S shape serpentine channel, the total flow of reagent is identical in each serpentine channel
First group of S shape serpentine channel 71, from left to right, the volume of three outlet outflow solution is 2/3, and concentration is respectively A, (A+B)/2, B;
Second group of S shape serpentine channel 72, from left to right, the volume of four outlet outflow solution is 1/2, and concentration is respectively A, (2A+B)/3, and (A+2B)/3, B;
The 3rd group of S shape serpentine channel 73, from left to right, the volume of five outlet outflow solution is 2/5, and concentration is respectively A, (3A+B)/4, (A+B)/2, (A+3B)/4, B;
The 4th group of S shape serpentine channel 74, from left to right, the volume of six outlet outflow solution is 1/3, and concentration is respectively A, (4A+B)/5, (3A+2B)/5, (2A+3B)/5, and (A+4B)/5, B;
The 5th group of S shape serpentine channel 75, from left to right, the volume of seven outlet outflow solution is 2/7, and concentration is respectively A, (5A+B)/6, (2A+B)/3, (A+B)/2, (A+2B)/3, (A+5B)/6, B;
The 6th group of S shape serpentine channel 76, from left to right, the volume of eight outlet outflow solution is 1/4, and concentration is respectively A, (6A+B)/7, (5A+2B)/7, (4A+3B)/7, (3A+4B)/7, (2A+5B)/7, (A+6B)/7, B.
If from the NaCl solution of a solution inlet port 3 inputs 0.9%, another solution inlet port 4 input pure water, then the NaCl solution concentration of eight detection cells 61～68 is respectively: 0.90%, 0.77%, 0.64%, 0.51%, 0.39%, 0.26%, 0.13%, and 0.
Method of inspection check speed of the present invention is fast, and manual intervention is few, has reduced simultaneously blood using amount, and the blood sample consumption can reduce to micro updating.
In above-described embodiment, S shape serpentine channel is adopted in the hybrid channel in the micro-fluidic chip, in the reality, can also adopt the serpentine channel of other shapes such as zigzag or bow font, and its function is that two kinds of solution that flow in it are fully mixed.
Claims (1)
1. micro-fluidic chip that is used for the check osmotic fragility, comprise chip body, it is characterized in that: two solution inlet port and a blood sample import are set on the described chip body, some detection cells are set in the chip body, described some detection cells are rods arranged in horizontal line, the degree of depth of detection cell is 30～60 microns, and they are communicated with the blood sample import by the blood sample microchannel, and is communicated with two solution inlet port by the microchannel network that automatically generates concentration gradient; The microchannel network of described automatic generation concentration gradient comprises some groups of hybrid channels that are arranged in parallel, organize to last from first group, the quantity of the hybrid channel that comprises increases progressively successively, the entrance of all hybrid channels in every group, and the outlet of all hybrid channels all is connected on the overall channel in upper one group, arrange in a triangle two hybrid channels adjacent with this hybrid channel in each hybrid channel and next group, and the overall channel equal in length in the outlet of each hybrid channel and next group between the entrance of two hybrid channels adjacent with this hybrid channel, the outlet correspondence of each hybrid channel is linked described some detection cells in last group, first group comprises three hybrid channels, the overall channel of first group of hybrid channel is communicated with described two solution inlet port in two diverse locations, and solution inlet port equates with passage length between the entrance of the first two hybrid channel in first group, and another solution inlet port equates with passage length between the entrance of latter two hybrid channel in first group.
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| CN103170377B (en) * | 2011-12-20 | 2015-02-18 | 中国科学院深圳先进技术研究院 | Hemocyte analysis chip and system for using chip thereof |
| CN102580798B (en) * | 2012-02-28 | 2014-03-05 | 东北大学 | Solution gradient dilution device with microfluidic chip |
| CN104498331B (en) * | 2015-01-08 | 2015-08-19 | 青岛大学 | The preparation method of the two concentration gradient micro-fluidic chip of a kind of single passage and application thereof |
| CN104849222B (en) * | 2015-01-23 | 2018-01-16 | 江苏大学 | The micro-fluidic apparatus for measuring concentration of rotation dish-style and method based on photometric detection |
| CN104962471B (en) * | 2015-06-11 | 2018-01-30 | 浙江大学 | A kind of entrance concentration gradient generator of modified two and its design method |
| CN106591105A (en) * | 2016-12-09 | 2017-04-26 | 东北大学 | Microorganism automatic sample introduction system based on microfluidic chip and preparation method thereof |
| CN107290294A (en) * | 2017-08-21 | 2017-10-24 | 杭州金域医学检验所有限公司 | Osmotic fragility detects screening technique and its application |
| CN109580485A (en) * | 2019-01-18 | 2019-04-05 | 大连理工大学 | A kind of fixation device and application method for red blood cell super-resolution imaging |
| CN114295533A (en) * | 2021-12-20 | 2022-04-08 | 上海原科实业发展有限公司 | Erythrocyte osmotic fragility determination method based on cell counting technology |
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| CN1588062A (en) * | 2004-09-29 | 2005-03-02 | 潘干华 | Method for determining red blood cell penetration fragility |
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| CN1588062A (en) * | 2004-09-29 | 2005-03-02 | 潘干华 | Method for determining red blood cell penetration fragility |
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