CN106885807B - Large-scale living organism screening system based on micro-fluidic technology - Google Patents
Large-scale living organism screening system based on micro-fluidic technology Download PDFInfo
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- CN106885807B CN106885807B CN201710093950.7A CN201710093950A CN106885807B CN 106885807 B CN106885807 B CN 106885807B CN 201710093950 A CN201710093950 A CN 201710093950A CN 106885807 B CN106885807 B CN 106885807B
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Abstract
The invention discloses a large-scale living organism screening system based on a microfluidic technology, which comprises: the system comprises a chip integrated container, a plurality of micro-fluidic chips are fixed in the chip integrated container according to preset positions, a microscope and a CCD camera are installed on an adjustable three-coordinate shaft frame, a computer controls the displacement of the adjustable three-coordinate shaft frame according to preset time points according to the preset positions, and focusing is realized by adjusting the displacement of a z axis, so that the microscope and the CCD camera can scan all the micro-fluidic chips according to the time point sequence, and clear large-scale and automatic image acquisition is realized.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to a large-scale living organism screening system based on a microfluidic technology.
Background
The micro-fluidic technology has the size matched with the micro-living organisms, and the controllable fluid of the micro-fluidic technology can capture and place the micro-living organisms on the micro-fluidic chip without mechanical damage, just can meet the requirement of high-throughput screening, complete the model establishment of various diseases, does not need transfer, and can directly receive drug stimulation to carry out the work of drug screening, metabolite analysis and the like.
At present, various microfluidic chips can provide various functions and can realize better process control and rapid analysis and reaction, but the existing microfluidic technology-based living organism screening system still has huge challenges in the aspects of automation, large scale and low cost.
Disclosure of Invention
The invention aims to provide a large-scale living organism screening system based on a microfluidic technology, which can realize clear large-scale and automatic image acquisition.
In order to solve the technical problems, the invention adopts the technical scheme that:
a large-scale living organism screening system based on microfluidic technology, comprising: a chip integrated container which fixes a plurality of microfluidic chips according to predetermined positions; an adjustable three-coordinate shaft bracket; the microscope and the CCD camera are arranged on the adjustable three-coordinate shaft bracket; and the computer controls the displacement of the adjustable three-coordinate shaft bracket according to a preset time point and the preset position so as to control the displacement of the microscope and the CCD camera, so that the displacement range of the microscope and the CCD camera covers all the microfluidic chips, and the computer also realizes focusing by adjusting the displacement of the z axis.
Compared with the prior art, the invention has the beneficial effects that:
the micro-fluidic chips are fixed in the chip integrated container according to preset positions, the microscope and the CCD camera are installed on the adjustable three-coordinate shaft frame, the computer controls the displacement of the adjustable three-coordinate shaft frame according to the preset positions according to preset time points, and focusing is realized by adjusting the displacement of the z axis, so that the microscope and the CCD camera can scan all the micro-fluidic chips according to the time point sequence, and clear large-scale and automatic image acquisition is realized.
In the biomedical research, not only the embryo of the organism is needed to be used as an animal experimental model, but also the hatched organism is a model object, so as to facilitate the image capture of the hatched organism and obtain a consistent image, the hatched organism needs to be fixed at a specific posture, and the traditional method needs tedious and multistep manual intervention, in the large-scale living organism screening system based on the microfluidic technology provided by the invention, an automatic microfluidic chip with a posture control function is preferably included, and the method specifically comprises the following steps:
the micro-fluidic chip comprises a containing hole for an incubated organism, the containing hole is composed of two layers, the size of the upper layer is larger than that of the incubated organism and is used for maintaining the survival of the incubated organism, the size of the lower layer is designed according to the size of the incubated organism in a specified posture, when the liquid extraction amount of the containing hole is increased, the liquid level height in the containing hole is reduced, the incubated organism descends to the lower layer of the containing hole along with fluid from the upper layer of the containing hole and is fixed according to the specified posture, and when the liquid level height in the containing hole is recovered, the incubated organism returns to the upper layer of the containing hole along with the fluid from the lower layer of the containing hole, so that the viability of the organism is ensured.
Furthermore, the containing holes are designed to be rectangular, and compared with the circular containing holes with the same area, the rectangular containing holes can increase the activity space and the survival rate of the hatched organisms in the microfluidic chip.
Furthermore, when the hatched organism is zebra juvenile fish, the containing hole is rectangular, the size of the lower layer can be designed to be 0.2mm multiplied by 4mm, the zebra juvenile fish is ensured to be fixed in the vertical posture capable of observing two eyes at the lower layer of the containing hole, and the method has great advantage in observing the development of heart, cerebral vessels and nervous system.
Preferably, the microfluidic chip in the large-scale living organism screening system based on the microfluidic technology provided by the invention can also realize the loading and accurate distribution of chemical reagents, and deliver different chemical reagents in different dosages, specifically:
the microfluidic chip also comprises a microfluidic concentration gradient generator, wherein the microfluidic concentration gradient generator consists of an upper layer and a lower layer, and the upper layer of the microfluidic concentration gradient generator connects the lower layer of the tree structure of the microfluidic concentration gradient generator with the containing hole.
According to the dynamic range of the required drug concentration in the specified drug determination, the lower layer of the microfluidic concentration gradient generator can be a two-inlet microfluidic concentration gradient generator or a three-inlet microfluidic concentration gradient generator.
In combination with the functions of the microfluidic chip, preferably, the large-scale living organism screening system based on the microfluidic technology provided by the invention comprises the microfluidic chip with a four-layer structure, can realize automatic loading of one or more organism embryos, automatically introduces the hatched organisms into the containing holes, controls the postures of the hatched organisms, and delivers different chemical reagents in different doses, and specifically comprises the following steps:
the microfluidic chip is composed of four layers, including: a microfluidic concentration gradient generator layer; the reagent enters the track layer; a housing hole and a reagent discharge rail layer; the device comprises a cover layer with an outlet connected with a recovery injector, wherein the four layers of cover layer are independently arranged and tightly adhered, a single-layer chip for loading embryos is detachably arranged at the upper end of the microfluidic chip, the size of a micro hole of the single-layer chip is designed to be capable of accommodating the volume of a single embryo, after the single-layer chip is loaded with a solution containing the embryos, the embryos are driven to flow towards the micro hole by reducing the liquid level height, so that each micro hole is filled with the single embryo, when the embryos are incubated, the liquid level height is further reduced, the incubated organisms are guided to enter the accommodating hole of the microfluidic chip, and the single-layer chip is detached to remove the shell of the embryos.
Further, in the large-scale living organism screening system based on the microfluidic technology provided by the invention, the system also comprises a pipeline box, the pipeline box is aligned with the microfluidic chip installed in the chip integrated container, and the experimental reagent can be rapidly transferred in the microfluidic chip and the injection pump through the pipeline box.
Further, the large-scale living organism screening system based on the microfluidic technology provided by the invention comprises a temperature controller, wherein the temperature controller is arranged below the chip integrated container and is used for providing the temperature from room temperature to 37 ℃ so as to meet different organism culture specifications.
Still further, the present invention provides a microfluidic based large scale living organism screening system comprising a gas inlet that can provide specific gases required for certain culture conditions.
Still further, the large-scale living organism screening system based on the microfluidic technology comprises a device consisting of an excitation light source and a multiband optical filter, and can be used for collecting fluorescence micrographs.
Furthermore, because polymethyl methacrylate is a thermoplastic material with excellent transparency and almost no chemical absorption, the microfluidic chip in the large-scale living organism screening system based on the microfluidic technology provided by the invention is made of polymethyl methacrylate.
Still further, the accommodating holes in the microfluidic chip in the large-scale living organism screening system based on the microfluidic technology are prepared by laser engraving.
Drawings
FIG. 1 is a schematic structural diagram of a large-scale living organism screening system based on microfluidic technology in an embodiment of the present invention;
fig. 2 (a) (b) (c) (d) (e) (f) is a structural diagram of a four-layer microfluidic chip of a large-scale living organism screening system based on microfluidic technology in an embodiment of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
Referring to fig. 1, an embodiment of the present invention provides a large-scale living organism screening system (for convenience of description, hereinafter referred to as a screening system) 10 based on a microfluidic technology, where the screening system 10 is in a box shape and has a volume of 30cm × 40cm × 40 cm. The structure of the screening system 10 is specifically:
the chip integrated container 101 is used for fixing a plurality of microfluidic chips 102 according to preset positions, the area of the chip integrated container is 200mm multiplied by 300mm, and at least 40 microfluidic chips 102 with the areas of 25 mm multiplied by 60 mm can be accommodated;
comprises an adjustable three-coordinate shaft bracket 103 controlled by a computer;
comprises a monocular optical microscope 104 (200-300 times magnification) and a 180 ten thousand pixel CCD camera 105 which are arranged on the adjustable three-coordinate shaft frame 103; the computer controls the displacement of the adjustable three-coordinate shaft frame 103 according to the preset time points and the preset positions of all the microfluidic chips 102, so that the displacement of the monocular optical microscope 104 and the CCD camera 105 is controlled, the displacement ranges of the monocular optical microscope 104 and the CCD camera 105 cover all the microfluidic chips 102, and the computer also realizes focusing by adjusting the displacement of the z axis;
and a tube cassette 106, wherein the tube cassette 106 is aligned with the microfluidic chip 102 mounted in the chip-integrated container 101, and the experimental reagent can be rapidly transferred in the microfluidic chip 102 and the syringe pump 107 through the tube cassette 106.
And the temperature controller is arranged below the chip integrated container 101 and used for providing the temperature from room temperature to 37 ℃ so as to meet different organism culture specifications.
Also included is a gas inlet 108, the gas inlet 108 providing specific gases required for certain culture conditions.
The device also comprises an excitation light source 109 and a multiband optical filter 110, and can collect fluorescence micrographs.
The upper part of the box body shell of the screening system 10 is also provided with a bubble level gauge 111, and the lower part is also provided with a level adjusting foot base 112, so that the box body can be ensured to be level.
In this embodiment, the microfluidic chip 102 used in the screening system 10 may be a microfluidic chip for loading embryos, or a microfluidic chip for dynamic organism culture and real-time imaging of incubated organisms, and when the microfluidic chip is loaded with the incubated organisms, the microfluidic chip 102 has a four-layer structure (fig. 2 (a)), including: a microfluidic concentration gradient generator layer (fig. 2 (b) is a two-inlet microfluidic concentration gradient generator layer, and fig. 2 (c) is a three-inlet microfluidic concentration gradient generator layer); reagent enters the track layer (fig. 2 (d)); a housing hole and a reagent discharge rail layer (FIG. 2 (e); a cover layer with an outlet connected to a recovery syringe (FIG. 2 (f)), which are independently arranged and closely adhered.
The single-layer chip for embryo loading is detachably arranged at the upper end of the microfluidic chip 102, the micro holes of the single-layer chip are designed to accommodate the volume of a single embryo, after the single-layer chip is loaded with a solution containing the embryo, the liquid level height is reduced to drive the embryo to flow towards the micro holes, so that each micro hole is filled with the single embryo, when the embryo is incubated, the liquid level height is further reduced, the incubated organism is guided to enter the accommodating hole of the microfluidic chip 102, and the single-layer chip is detached to remove the shell of the embryo.
The containing holes of the microfluidic chip 102 are used for containing incubated organisms, the containing holes are rectangular and 48 in number, the containing holes are prepared by laser engraving, and are formed by two layers according to the requirement of an automatic microfluidic chip with a posture control function, the size of the upper layer is larger than that of the incubated organisms and is used for maintaining the survival of the incubated organisms, the size of the lower layer is designed according to the size of the incubated organisms under a specified posture, when the liquid extraction amount of the containing holes is increased and the liquid level height in the containing holes is reduced, the incubated organisms fall to the lower layer of the containing holes along with the fluid from the upper layer of the containing holes and are fixed according to the specified posture, and when the liquid level height in the containing holes is restored, the incubated organisms return to the upper layer of the containing holes along with the fluid from the lower layer of the containing holes.
The holding hole designed according to the size of the incubated organism can realize the control of the posture, and the incubated organism can be transferred to the holding hole with limited geometrical structure in a specific posture by adjusting the liquid level height.
The microfluidic concentration gradient generator layer on the microfluidic chip 102 includes a microfluidic concentration gradient generator for delivering and accurately dispensing chemical reagents (e.g., drug candidates, nucleic acids, proteins/enzymes, or labeled antibodies). The microfluidic concentration gradient generator consists of an upper layer and a lower layer, wherein the upper layer of the microfluidic concentration gradient generator connects the containing hole with the lower layer of the tree structure of the microfluidic concentration gradient generator. The lower layer structure can be changed into a three-inlet microfluidic concentration gradient generator from a two-inlet microfluidic concentration gradient generator. For example, in a two-inlet microfluidic concentration gradient generator, the lowest drug concentration that can be achieved is 6.3%; whereas in a three-inlet microfluidic concentration gradient generator, the concentration gradient can be varied by a third inlet in the center. For example, 100% drug, 10% drug, and buffer are injected into the microfluidic chip, a drug concentration of a minimum of 1.3% can be achieved.
The outlets of the microfluidic chip 102 are respectively connected with different injectors, so that waste liquid can be recovered. Subsequent HPLA or GC-MS analysis can compare the compositional changes of the import and export agents, metabolism and absorption by the organism at different drug concentrations, and can provide additional drug metabolism information.
The screening system 10 provided in this embodiment combines computer-controlled xyz-axis displacement and real-time image acquisition procedures: image acquisition of a large area (200 mm x 300 mm) can be achieved by a monocular optical microscope and a high-resolution CCD camera mounted on the displacement axis, and by adjusting the z-axis focus. Through computer control, the experimental data of each organism in the microfluidic chip can be collected according to the time point sequence.
The screening system 10 can handle up to 1920 independent organisms exposed to 240 gradient levels after full loading and can simultaneously examine up to 40 drugs or drug combinations. Once all microfluidic chips are fixed in the chip integration container, the rest of the experimental operations can be completed by computer automation. This screening system 10 not only saves time in photographing individual organisms each day, but also allows continuous monitoring of the organism culture progress for a long period of time (lasting two days), which is a significant challenge to data collection using conventional methods.
The screening system of the embodiment of the present invention will be described below by using a specific application test example, and the application object of the screening system is zebra fish.
Doxorubicin is a known chemotherapeutic agent. However, the dosage of clinical medication is limited by its strong side effects. In the test, adriamycin is selected as a model drug to construct a zebra fish juvenile fish cardiotoxicity model, such as heart rate hypofunction or heart hemorrhage. 100mg/L of doxorubicin solution and E3 zebrafish medium containing 0.2mM Phenylthiourea (PTU) were pre-filled in syringes and attached to the microfluidic chips of a two-inlet microfluidic concentration gradient generator, respectively. The syringe pump can continuously provide stable liquid flow to the two-inlet microfluidic concentration gradient generator during the zebra fish breeding period. The tree structure of the two-inlet microfluidic concentration gradient generator can generate 6 different concentration gradients through controlled laminar flow and diffusion mixing.
Embryos were obtained from wild type zebrafish by random mating. Fertilized eggs were collected and transferred to a petri dish with E3 medium and incubated in an incubator at 28.5 ℃. After 24 hours, 0.2mM Phenylthiourea (PTU) was added to the E3 medium to inhibit melanogenesis in zebrafish. Zebrafish are typically hatched at 40 hpf (hours after fertilization) and 48 hpf young fish are transferred to containment wells within the microfluidic chip as described in the previous examples. There are 8 individual containment wells per concentration gradient, which can provide enough replicate samples to test for the dose effect of the drug candidate. All the containing holes are wrapped by a gas-permeable membrane, and then the microfluidic chip is fixed into a chip integrated container of the screening system according to a predetermined position.
The tubing connection was then initiated and after the connection check was complete, the inlet and outlet syringe pumps were started to balance the total flow into and out (75 ul/h inlet and 25ul/h outlet). Under the control of a computer, the displacement of the adjustable three-coordinate shaft bracket is controlled according to a preset time point, so that the displacement of the microscope and the CCD camera is controlled to the first containing hole, and the computer controls the displacement of the z axis to focus the camera and the optical microscope system with the first containing hole, so that a clear heartbeat visual field is obtained.
Once the focal length of the first containing hole is fixed, the subsequent containing holes can be automatically positioned and focused through a computer, and the image acquisition of all the containing holes is completed. For cardiotoxicity measurements, the heart beats of young fish were recorded using a short video recording for 20 seconds. Data acquisition for a total of 48 chips can be completed in about 10 minutes. Compared with the traditional method, the method has the advantage that only 2-3 juvenile fishes can be collected within 10 minutes. The determination of Dox cardiotoxicity requires 48 hours of drug treatment on the chip platform, which is the same as the conventional method but can greatly shorten the time interval for data acquisition. In addition to allowing large scale testing, the screening system also allows data collection of the same juvenile fish at different time points, which is nearly impossible with conventional methods.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (4)
1. A large-scale living organism screening system based on microfluidic technology, comprising: a chip integrated container which fixes a plurality of microfluidic chips according to predetermined positions; an adjustable three-coordinate shaft bracket; the microscope and the CCD camera are arranged on the adjustable three-coordinate shaft bracket; the computer controls the displacement of the adjustable three-coordinate shaft bracket according to a preset time point and the preset position, so that the displacement of the microscope and the CCD camera is controlled, the displacement range of the microscope and the CCD camera covers all the microfluidic chips, and the computer also realizes focusing by adjusting the displacement of the z axis;
the microfluidic chip is composed of four layers, including: a microfluidic concentration gradient generator layer; the reagent enters the track layer; a housing hole and a reagent discharge rail layer; the four layers of covering layers are independently arranged and tightly adhered, a single-layer chip for loading embryos is detachably placed at the upper end of the microfluidic chip, the size of the micro-hole of the single-layer chip is designed to accommodate the volume of a single embryo, after the single-layer chip is loaded with a solution containing the embryos, the single-layer chip drives the embryos to flow towards the micro-hole by reducing the liquid level height, so that each micro-hole is filled with the single embryo, when the embryos are incubated, the liquid level height is further reduced, the incubated organisms are guided to enter the accommodating hole of the microfluidic chip, the accommodating hole is formed by two layers, the size of the upper layer is larger than the size of the incubated organisms, the size of the lower layer is designed according to the size of the incubated organisms under a specified posture, and when the liquid extraction amount of the accommodating hole is increased, the liquid level in the accommodating hole is reduced, the incubated organisms drop from the upper layer of the containing hole to the lower layer of the containing hole along with the fluid and are fixed according to a specified posture, and when the liquid level height in the containing hole is recovered, the incubated organisms return to the upper layer of the containing hole from the lower layer of the containing hole along with the fluid;
the upper layer of the microfluidic concentration gradient generator connects the lower layer of the tree-shaped structure of the microfluidic concentration gradient generator with the containing hole;
the single-layer chip is disassembled to remove the shell of the embryo.
2. The microfluidic technology-based large-scale living organism screening system according to claim 1, further comprising a tube cassette aligned with the microfluidic chip mounted in the chip-integrated container, through which experimental reagents can be rapidly transferred in the microfluidic chip and the syringe pump.
3. The microfluidic technology based large-scale living organism screening system according to claim 2,
the temperature controller is arranged below the chip integrated container and is used for providing the temperature from room temperature to 37 ℃ so as to meet different organism culture specifications;
also comprises a gas inlet for providing specific gas required by certain culture conditions;
the device also comprises an excitation light source and a multiband optical filter, and is used for collecting fluorescence micrographs.
4. The large-scale living organism screening system based on the microfluidic technology as claimed in claim 3, wherein the microfluidic chip is made of polymethyl methacrylate, and the containing hole in the microfluidic chip is prepared by laser engraving.
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| CN109317225A (en) * | 2017-07-31 | 2019-02-12 | 中国科学院大连化学物理研究所 | It is a kind of based on digital microcurrent-controlled moveable magnet device |
| TWI690703B (en) * | 2017-12-12 | 2020-04-11 | 國立成功大學 | Microscopic imaging instrument for microfluidic chip |
| US11618025B2 (en) * | 2018-08-01 | 2023-04-04 | University Of Macau | Apparatus and method for on-chip microfluids dispensing |
| CN112113904A (en) * | 2020-09-18 | 2020-12-22 | 南京理工大学 | Micro-fluidic optical observation system and method for gas gradient driven macromolecule translation |
| CN112973814B (en) * | 2021-03-03 | 2022-03-18 | 北京理工大学 | Interlayer automatic alignment bonding device and method for multilayer microfluidic chip |
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| GB0321158D0 (en) * | 2003-09-10 | 2003-10-08 | Central Research Lab Ltd | Apparatus and method for handling cells,embryos or oocytes |
| JP2011062119A (en) * | 2009-09-16 | 2011-03-31 | Seiko Epson Corp | Chip for quantitatively determining biological sample |
| CN102757886A (en) * | 2011-04-27 | 2012-10-31 | 北京大学 | Microfluidic chip applicable to research on cell migration |
| CN103461279B (en) * | 2012-06-08 | 2015-11-18 | 中国科学院上海生命科学研究院 | For the micro flow chip of culture of nematodes and/or observation and equipment and application thereof |
| US9784663B2 (en) * | 2012-07-27 | 2017-10-10 | Engender Technologies Limited | Method and system for microfluidic particle orientation and/or sorting |
| CN103033497B (en) * | 2012-12-25 | 2014-10-15 | 吉林大学 | Microfluidic chip analyzer applying raman spectrum for detection |
| CN103695313B (en) * | 2013-12-10 | 2015-06-17 | 西安电子科技大学 | Automatic egg cell capturing and culturing device |
| CN106153879A (en) * | 2015-04-08 | 2016-11-23 | 李木 | Microfluidic system and the diagnostic method thereof of medical diagnosis on disease is realized with activity tiny organism |
| CN106244575B (en) * | 2016-08-02 | 2019-09-27 | 河海大学常州校区 | A kind of cell attitude control method and omnibearing observation method |
| CN106179548B (en) * | 2016-08-02 | 2018-11-09 | 河海大学常州校区 | A kind of control method for the micro-fluidic chip that microscopic particles are rotated around three axes |
| CN106190830B (en) * | 2016-08-02 | 2019-06-04 | 河海大学常州校区 | Make the experimental system and its working method of three-dimensional rotation for controlling cell |
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