CN113684129A - Embryo detection micro-fluidic chip and embryo detection system - Google Patents
Embryo detection micro-fluidic chip and embryo detection system Download PDFInfo
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Abstract
The invention discloses an embryo detection micro-fluidic chip and an embryo detection system. The first aspect of this application provides embryo detection micro-fluidic chip, and this embryo detection micro-fluidic chip includes that the flow direction along the culture solution sets gradually: an embryo culture chamber for culturing embryos and capable of intercepting the embryos to allow culture fluid to flow out of the embryo culture chamber; and the detection chamber is communicated with the embryo culture chamber and is used for accommodating the culture solution flowing out of the embryo culture chamber and detecting the culture solution. The microfluidic chip for embryo detection at least has the following beneficial effects: the embryo detection microfluidic chip separates the culture area and the detection area of the embryo, so that the culture solution with the nutrient substances taken and the content of the embryo metabolic waste increased in the culture process can directly flow into a downstream detection chamber for detection, the embryo pollution caused by in-situ detection is avoided, and the embryo can be directly recovered after the detection is finished.
Description
Technical Field
The application relates to the technical field of medical engineering, in particular to an embryo detection microfluidic chip and an embryo detection system.
Background
The assisted reproduction technology, namely In vitro fertilization-Embryo transfer (IVF-ET), is the most effective means for treating infertility at present. Since the first "tube baby" birth in 1978, the technology has undergone the evolution of the three generations of traditional in vitro fertilization, intracytoplasmic sperm injection and preimplantation embryo genetic diagnosis technology for over forty years. During the course of treatment, the most developmentally potential embryos are often selected from a plurality of embryos from a patient for transplantation. In order to ensure successful transplantation, multiple embryos are sometimes transplanted simultaneously, which often causes complications of multiple embryo pregnancies. In order to improve the success rate of IVF-ET and reduce complications, single embryo transfer is becoming a trend. Therefore, screening of high quality embryos with high developmental potential becomes a key factor for the treatment of infertility.
Currently, embryo screening still stays at the aspect of morphological observation, namely, evaluation is carried out according to morphological characteristics of embryos in different development stages. As each evaluation index is judged by visual inspection, the subjectivity is strong. In addition, the embryo is three-dimensional and has more cells, so that the human eye can have deviation through microscopic observation, and misjudgment on the quality of the embryo can be caused. Microfluidic technology (Microfluidics) integrates basic steps of sample preparation, reaction, separation, detection and the like in an analysis process on a micron-scale chip, and is widely applied in related fields of cell culture, cell analysis, biochemical detection and the like, but is less applied to embryo screening. Although attempts have been made to monitor changes in glucose, lactate and dissolved oxygen during embryo development using microfluidic chips, they are prone to contamination of the embryos and are difficult to recover after detection.
Disclosure of Invention
The present application is directed to solving at least one of the problems in the prior art. Therefore, the application provides the embryo detection micro-fluidic chip which is less in pollution and convenient to recover.
The application also provides an embryo detection system which is less in pollution and convenient to recover.
The first aspect of this application provides embryo detection micro-fluidic chip, and this embryo detection micro-fluidic chip includes that the flow direction along the culture solution sets gradually:
an embryo culture chamber for culturing embryos and capable of intercepting the embryos to allow culture fluid to flow out of the embryo culture chamber;
and the detection chamber is communicated with the embryo culture chamber and is used for accommodating the culture solution flowing out of the embryo culture chamber and detecting the culture solution.
The microfluidic chip for embryo detection according to the embodiment of the application has at least the following beneficial effects:
the embryo detection micro-fluidic chip provided by the embodiment of the application separates the culture area and the detection area of the embryo from each other, so that the culture solution after the nutrient substances are absorbed and the content of the metabolic waste of the embryo is improved in the culture process can directly flow into a downstream detection chamber for detection, the embryo pollution caused by in-situ detection is avoided, and the embryo can be directly recovered after the detection is finished.
In some embodiments of the present application, the embryo culture chamber is provided with a first liquid outlet, the embryo culture chamber is communicated with the detection chamber through the first liquid outlet, and the first liquid outlet is sized to intercept the embryo and allow the culture liquid to flow out of the embryo culture chamber. The size of the first liquid outlet is adjusted to enable the culture solution to flow out and the embryo to be kept in the embryo culture chamber, so that the embryo can grow by using the newly flowing culture solution at any time. In addition, the size of the first liquid outlet can be adjusted quickly in the preparation process of the embryo detection microfluidic chip, and the preparation of the product is facilitated.
In some embodiments of the present application, the embryo culture chamber is provided with an opening sized to enable an embryo to be fed into and removed from the embryo culture chamber through the opening. Set up the opening on embryo culture room, can send into and carry out more convenient when retrieving the operation to the embryo after finishing detecting the embryo before detecting.
In some embodiments of the present application, the microfluidic chip for embryo detection is further provided with a sealing plug for closing and opening the opening. Through the arrangement of the seal block, the embryo detection microfluidic chip keeps a closed state in the culture process of the embryo, so that the interference of the external environment is isolated, and the embryo metabolites and the like in the culture solution can be conveniently detected.
In some embodiments of the present application, a backflow prevention portion is provided between the embryo culture chamber and the detection chamber. Through setting up backflow prevention portion for the culture solution that flows out by embryo culture room can not take place to flow backward and arouse the pollution of embryo because of various reasons, causes the inaccurate of testing result and influences follow-up recovery to the embryo.
In some embodiments of the present application, the detection chamber is provided with an electrochemical reaction unit comprising a three-electrode system for detecting embryo metabolites in the culture solution. The three-electrode system refers to a three-electrode system comprising a working electrode, a reference electrode and an auxiliary electrode. The three-electrode system is used for quickly and effectively detecting the components in the culture solution flowing into the detection chamber.
In a third aspect of the application, an embryo detection system is provided, which comprises the above-mentioned embryo detection microfluidic chip.
The embryo detection system according to the embodiment of the application has at least the following beneficial effects:
in the embryo detection system, the culture area and the detection area of the embryo are separated from each other, so that a culture solution with the nutrient substances taken and the content of the metabolic waste of the embryo improved in the culture process can directly flow into a downstream detection chamber for detection, the embryo pollution caused by in-situ detection is avoided, and the embryo can be directly recovered after the detection is finished.
In some embodiments of the present application, the apparatus further comprises an optical detection unit for performing morphological detection on the embryo fed into the embryo culture chamber. The embryo in the embryo culture chamber is morphologically detected by the arrangement of the optical detection unit, so that more accurate judgment can be made on the quality and development potential of the embryo by integrating various morphological and physiological indexes, and the problem of insufficient index evaluation dimensionality in a single aspect is avoided.
In some embodiments of the present application, the device further comprises a gas-liquid mixing unit, the gas-liquid mixing unit is communicated with the embryo culture chamber, and the gas-liquid mixing unit is used for supplying culture solution to the embryo culture chamber. Through the setting of gas-liquid mixing unit for the embryo is in complete airtight state in the culture process, thereby is aided with the in vivo microenvironment of culture solution simulation fallopian tube better.
In some embodiments of the present application, a gas-liquid mixing unit includes:
the liquid storage device is communicated with the embryo culture chamber and is used for containing a culture solution;
the gas input module is used for introducing gas with preset content into the liquid storage device, and the gas comprises oxygen and carbon dioxide.
The gas input module is arranged to introduce oxygen and carbon dioxide with preset content into the culture solution, so that the culture solution has expected dissolved oxygen and carbon dioxide, the culture solution can provide a proper amount of oxygen for the growth of the embryo besides providing nutrition for the embryo, and the microenvironment in the body can be better simulated.
In some embodiments of the present application, the gas input module comprises:
the oxygen input module is used for introducing oxygen with preset content into the liquid storage device;
and the carbon dioxide input module is used for introducing carbon dioxide with preset content into the liquid storage device.
Through setting up oxygen input module and carbon dioxide input module respectively, can in time adjust the content of dissolved oxygen and carbon dioxide in the culture solution according to the detection to the culture solution in detecting the room under some circumstances to adjust the growth of embryo.
In some embodiments of the present application, the gas input module further comprises a nitrogen gas input module for introducing a predetermined content of nitrogen gas.
Additional aspects and advantages of the present application will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the present application.
Drawings
Fig. 1 is a schematic structural diagram of an embryo detection microfluidic chip according to an embodiment of the present application.
FIG. 2 is a schematic cross-sectional view of an embryo culture chamber according to one embodiment of the present application.
FIG. 3 is a schematic illustration of the manner in which embryos are fed into the embryo culture chamber according to one embodiment of the present application.
FIG. 4 is a schematic of a three-electrode system of one embodiment of the present application.
FIG. 5 is a schematic view of an embryo detection system according to one embodiment of the present application.
Reference numerals: the embryo culture chamber 100, the detection chamber 110, the backflow prevention part 120, the culture solution inlet 130, the waste liquid outlet 140, the first detection solution inlet 150, the second detection solution inlet 160, the electrode external interface 170, the embryo 200, the first liquid inlet 211, the first liquid outlet 212, the opening 213, the sealing plug 220, the suction head 300, the three-electrode system 400, the working electrode 410, the disc end 411, the reference electrode 420, the first arc segment 421, the counter electrode 430, the second arc segment 431, the embryo detection microfluidic chip 500, the heating plate 510, the waste liquid tank 511, the detection liquid tank 512, the gas-liquid mixing unit 520, the temperature regulation device 521, the oxygen input module 522, the carbon dioxide input module 523, the nitrogen input module 524, the liquid reservoir 525, the objective 531, the total reflection mirror 532, the imaging device 533, the moving platform 534, and the information processing device 540.
Detailed Description
The conception and the resulting technical effects of the present application will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, and not all embodiments, and other embodiments obtained by those skilled in the art without inventive efforts based on the embodiments of the present application belong to the protection scope of the present application.
The following detailed description of embodiments of the present application is provided for the purpose of illustration only and is not intended to be construed as a limitation of the application.
In the description of the present application, the meaning of a plurality is one or more, the meaning of a plurality is two or more, and the above, below, exceeding, etc. are understood as excluding the present number, and the above, below, within, etc. are understood as including the present number. If the first and second are described for the purpose of distinguishing technical features, they are not to be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated or implicitly indicating the precedence of the technical features indicated.
In the description of the present application, unless otherwise expressly limited, terms such as set, mounted, connected and the like should be construed broadly, and those skilled in the art can reasonably determine the specific meaning of the terms in the present application by combining the detailed contents of the technical solutions.
In the description of the present application, reference to the description of the terms "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present application. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Referring to fig. 1, the microfluidic chip for embryo culture according to an embodiment of the present application includes an embryo culture chamber 100 and a detection chamber 110 sequentially arranged along a flowing direction of a culture solution (direction of arrow in the figure), the embryo culture chamber 100 is used for culturing an embryo and can intercept the embryo in the embryo culture chamber 100 so that the culture solution can flow out of the embryo culture chamber 100, the detection chamber 110 is communicated with the embryo culture chamber 100, the culture solution flowing out of the embryo culture chamber 100 flows into the detection chamber 110, and the detection chamber 110 can detect the flowing culture solution. By the method, the embryo detection microfluidic chip separates the culture area and the detection area of the embryo, so that nutrient substances are taken in during the culture process and culture solution which generates a certain amount of embryo metabolic waste can directly flow into the downstream detection chamber 110 from the embryo culture chamber 100 for detection, embryo pollution caused by direct in-situ detection in the embryo culture chamber 100 is avoided, and the embryo can be directly recovered after the detection is finished.
Reference is made to FIG. 2, which is a schematic cross-sectional view of an embryo culture chamber in some embodiments of the present application. With reference to fig. 1 and 2, the embryo culture chamber 100 is provided with a first liquid inlet 211 and a first liquid outlet 212, the embryo culture chamber 100 is communicated with the detection chamber 110 through the first liquid outlet 212, and the first liquid outlet 212 is configured to intercept the embryo 200 so that the embryo cannot flow out of the embryo culture chamber 100 and the culture liquid can flow out of the embryo culture chamber 100. By defining the size of first outlet port 212 to be smaller than the size of embryo 200, embryo 200 is retained in embryo culture chamber 100, so that embryo 200 can be grown with the latest inflow culture solution at any time without the problem of in situ detection that embryo 200 cannot be recycled. The mode of adjusting the first liquid outlet 212 can be quickly realized in the preparation process of the embryo detection microfluidic chip, and the preparation of the product is convenient.
Reference is made to FIG. 3, which is a schematic illustration of embryo transfer in some embodiments of the present application. In some embodiments, and with reference to FIGS. 2 and 3, embryo culture chamber 100 is further provided with an opening 213, opening 213 being sized to allow an embryo 200 to be transferred into and out of embryo culture chamber 100 through opening 213. Through the arrangement of the opening 213, the embryo 200 before detection can be more conveniently sent in and recovered. In some embodiments, a sealing plug 220 is further disposed at a position corresponding to the opening 213, and the sealing plug 220 is used for closing and opening the opening 213. By arranging the sealing block 220, after the embryo 200 is sent into the embryo culture chamber 100 through the suction head 300, the opening 213 can be sealed by the sealing block 220, so that the embryo culture chamber 100 is kept in a sealed state, the interference of the external environment is isolated, and the detection of embryo metabolites in the culture solution is convenient.
Referring to FIG. 1, in some embodiments of the present application, a backflow preventer 120 is also provided between the embryo culture chamber 100 and the detection chamber 110. The specific shape and structure of the backflow prevention part 120 can be set according to conventional knowledge in the art, and a specific implementation manner can be to provide a backflow prevention valve structure in the flow channel between the embryo culture chamber 100 and the detection chamber 110, or to set the part of the flow channel to have a change in height direction, such as an inverted U-shaped structure, so that the backflow of the culture solution needs to work against additional gravity to prevent the backflow thereof, and the like. The backflow prevention part 120 can ensure that the culture solution flowing out of the embryo culture chamber 100 cannot cause embryo pollution due to backflow into the embryo culture chamber 100, and further cause inaccurate detection results and influence on subsequent embryo recovery.
Referring to fig. 1, in some embodiments of the present application, an electrochemical reaction unit is disposed in the detection chamber 110, and the target molecule in the culture solution is detected by the electrochemical reaction unit to determine the condition of the embryo. In some specific embodiments thereof, the electrochemical reaction cell comprises a three-electrode system. In some embodiments, the three-electrode system is connected to the external electrode interface 170.
In some embodiments of the present application, a three-electrode system is configured as shown in fig. 4, the three-electrode system 400 includes a working electrode 410, a reference electrode 420, and a counter electrode 430, the working electrode 410 has a disk end 411, the reference electrode 420 is located outside the disk end 411 of the working electrode 410, and the reference electrode 420 includes a first circular arc segment 421 concentric with the disk end 411 of the working electrode 410; the counter electrode 430 is also located outside the disk end 411 of the working electrode 410, and the counter electrode 430 includes a second arc segment 431 concentric with the disk end 411 of the working electrode 410, and the first arc segment 421 and the second arc segment 431 enclose the disk end 411. In some of these approaches, working electrode 410 is performed by an enzyme-catalyzed reaction. The enzyme catalysis detection may be performed by fixing an enzyme electrode, which is formed by an enzyme capable of performing an enzyme catalysis reaction with the analyte molecules in the culture solution, on the disc end 411 in advance, and detecting the concentration of the analyte by using the change of an electrical signal during the reaction between the analyte and the enzyme. Also, the enzyme may be injected into the detection chamber before detection in the form of a solution and fixed to the electrode to participate in the reaction so that the change in the electrical signal is detected by the three-electrode system 400 composed of the working electrode 410 and the like. For example, when the glucose content in the culture solution is measured, a glucolase electrode or a glucolase solution is used for the measurement; and when detecting the urea content in the culture solution, detecting by adopting a urease electrode or a urease solution. The arc design of the first arc segment 421 and the second arc segment 431 may enhance the electrical signal to some extent. In some embodiments, the intensity of the electrical signal is directly related to the concentration of the substance to be detected in the culture medium, so that the concentration of the substance to be detected in the culture medium after embryo consumption can be determined according to the intensity of the electrical signal.
Referring to fig. 1, in some specific embodiments, the microfluidic chip for embryo detection is provided with a culture solution inlet 130 and a waste solution outlet 140, wherein a culture solution is injected into the embryo culture chamber 100 of the microfluidic chip for embryo detection through the culture solution inlet 130, and the culture solution after absorbing nutrition and discharging metabolic waste through the embryo is discharged from the waste solution outlet 140 after the detection of the detection chamber 110 is completed.
Referring to fig. 1, in some embodiments, the microfluidic chip for embryo detection has two embryo culture chambers 100, and each embryo culture chamber 100 can be loaded with one embryo at a time, so that two embryos can be cultured and detected simultaneously. Further, for each embryo culture chamber 100, two detection chambers 110 may be connected simultaneously to form one group, and there are two groups of four detection chambers 110, so that different objects to be detected in the culture solution are detected in different detection chambers 110 corresponding to the same embryo culture chamber 100, respectively, to obtain multiple index parameters of the culture solution. In this case, the microfluidic chip for embryo detection is provided with waste liquid outlets 140 corresponding to the number of the detection chambers 110, and further provided with a first detection liquid injection port 150 and a second detection liquid injection port 160, wherein the first detection liquid injection port 150 is respectively communicated with one detection chamber 110 of each of the two groups of detection chambers 110, and can inject a first detection liquid participating in a detection reaction of a first object to be detected into the detection chamber 110; the second detecting liquid inlet 160 is respectively connected to the other detecting chamber 110 of the two detecting chambers 110, and can inject the second detecting liquid participating in the detecting reaction of the second analyte into the other detecting chamber 110. In addition, the detection chamber 110 may be cleaned by injecting a cleaning solution into the detection chamber 110 through the first and second detection liquid injection ports 150 and 160. Through the selection of each part of pump body, the automatic conveying of culture solution, detection solution and cleaning solution can be realized, and the pump bodies such as a pressure pump, an injection pump, a peristaltic pump and the like can be selected for the pumping of the detection solution and the cleaning solution.
In some embodiments, one of the embryo culture chambers 100 may be used as a reference, without directly participating in culturing the embryo, and the collected data is used as an initial value for the culture medium, while the other embryo culture chambers 100 are used to culture the embryo and are detected by the corresponding detection chambers 110, and the detected data is used as the data of the culture medium after embryo depletion, and the consumption of each embryo is obtained by subtracting the initial value from each set of data. On this basis, a larger number of embryo culture chambers 100, detection chambers 110 and other corresponding structures may be provided on the embryo detection microfluidic chip in order to detect more embryos simultaneously, and/or to detect more physiological parameters of the embryos.
The embodiment of the present application further provides an embryo detection system, which refers to fig. 5, and includes the above-mentioned embryo detection microfluidic chip 500, in some embodiments, the waste liquid outlet is further connected to a waste liquid tank 511, the detection liquid injection port is further connected to a detection liquid tank 512, the detection liquid required before detection is injected into the detection chamber 110 through the corresponding detection liquid inlet by the detection liquid tank 512, and the waste liquid after detection is discharged into the waste liquid tank 511 through the corresponding waste liquid outlet. In addition, a heating plate 510 is further disposed at the bottom of the microfluidic chip 500 for embryo detection, so that the injected culture solution can be properly heated to better simulate the temperature conditions of the micro environment in which the embryo 200 is located.
Referring to fig. 5, in some specific embodiments, the embryo detection system further includes an optical detection unit and an electrochemical reaction unit, the optical detection unit is configured to perform morphological detection on the embryo 200 in the embryo culture chamber 100, and the three-electrode system 400 of the electrochemical reaction unit is configured to perform detection on the embryo metabolite in the detection chamber 110, so that the quality and the development potential of the embryo 200 can be more accurately determined by integrating various indexes such as morphology and physiology. In some embodiments, the optical detection unit includes an objective 531, a total reflection mirror 532 and an imaging device 533, the optical information of the embryo 200 is collected by the objective 531, passes through the total reflection mirror 532 and finally is fed back to the imaging device 533, and the imaging device 533 can be a camera or a video camera, so that the embryo 200 can be imaged at intervals or continuously according to actual requirements. In some embodiments, the objective 531, the total reflection mirror 532 and other components in the optical detection unit are disposed on the moving platform 534, and the plurality of embryos 200 at different positions of the embryo detection microfluidic chip 500 can be optically imaged by the movement of the moving platform 534 to complete morphological detection. In some embodiments, imaging device 533 may also be connected to information processing device 540 (e.g., a computer) via wires or wirelessly, and may be capable of transmitting optical imaging data of embryo 200 to information processing device 540. The information processing device 540 may receive detection data of the culture solution from the electrochemical reaction unit directly or indirectly, and may process and analyze both the detection data and the detection data.
Referring to fig. 5, in some embodiments of the present application, the embryo detection system further comprises a gas-liquid mixing unit 520, wherein the gas-liquid mixing unit 520 comprises a liquid reservoir 525 and a gas input module, the liquid reservoir 525 is communicated with the embryo culture chamber 100, and the liquid reservoir 525 contains culture solution. The gas input module is used for introducing gas with preset content into the liquid storage device 525, the gas comprises oxygen and carbon dioxide, and the culture solution can provide proper oxygen for the growth of the embryo besides providing nutrition for the embryo by introducing the oxygen and the carbon dioxide with the preset content into the culture solution, so that the microenvironment in the body can be better simulated. In some embodiments, the gas input module comprises an oxygen input module 522, a carbon dioxide input module 523, and a nitrogen input module 524, which are used to introduce predetermined amounts of oxygen, carbon dioxide, and nitrogen into the reservoir 525, respectively. The oxygen input module 522, the carbon dioxide input module 523 and the nitrogen input module 524 may further include adjustable solenoid valves, and the input amounts of the oxygen input module 522, the carbon dioxide input module 523 and the nitrogen input module 524 are adjusted by adjusting the opening degrees of the solenoid valves, so that the carbon dioxide and the oxygen in the gas-liquid mixing unit 520 are maintained at the required proportional concentrations. The liquid reservoir 525 inputs the culture solution into the embryo detection microfluidic chip 500 through a culture solution delivery pump (not shown in the figure), and the culture solution delivery pump can be selected from common pumps with corresponding functions, such as a peristaltic pump, a pressure pump and the like. In some specific embodiments, the liquid reservoir is provided with an air outlet and an air inlet, when the culture fluid delivery pump is a pressure pump, the outlet of the pressure pump is connected with the air inlet of the liquid reservoir 525 through an air pipe, and in operation, the air outlet of the liquid reservoir 525 needs to be sealed, and compressed air of carbon dioxide and oxygen in a proper proportion is provided through the pressure pump. When the culture solution delivery pump is a peristaltic pump or a syringe pump, the air inlet and the air outlet of the liquid reservoir 525 are kept in an open state, and the proportional concentration of carbon dioxide and oxygen inside the gas-liquid mixing unit 520 needs to be maintained. In some embodiments, the embryo detection system uses a Flow-stop (Flow-stop) culture medium injection mode through a culture medium delivery pump, so that the embryo can sufficiently consume nutrients in the culture medium, and the requirement on a detection element in the detection chamber is reduced. In some specific embodiments, a temperature adjusting device 521 is further disposed in the gas-liquid mixing unit 520, and the temperature of the liquid in the gas-liquid mixing unit 520 is adjusted by the temperature adjusting device 521, so that the temperature of the culture solution is controlled within a desired range, and the culture solution is convenient to store.
In some embodiments, the embryo detection system further comprises an electrochemical workstation, wherein the electric signal detected by the detection chamber is collected and detected by the electrochemical workstation, and the electrochemical workstation can be further communicated with the information processing device. The information processing device can realize more accurate detection of the quality of the embryo through physiological and biochemical parameters obtained by electrochemical signals of the detection chamber and morphological parameters obtained by detection of the optical detection unit.
In some specific embodiments, the workflow of the embryo detection system provided herein is as follows:
1) and setting the position of the mobile platform to be moved for detection. The embryo detection microfluidic chip can be provided with more than two groups of embryo culture chambers and is used for simultaneously culturing one or more embryos. Therefore, the position where the objective lens moves can be set as required. Setting array A[i]＝{A1,A2,A3……Ai}，AiThe position at which the platform is moved each time.
2) The number j of the embryo culture chambers to be tested is set. Setting array B[j]＝{B1,B2,B3……Bj}，BjRepresents each embryo culture chamber of the embryo detection microfluidic chip.
3) And setting the number k of the physiological and biochemical indexes to be detected. Setting array C[k]＝{C1,C2,C3……Ck}，CkRepresenting k physiological and biochemical indicators such as glucose, dissolved oxygen, lactic acid, pH and active oxygen. Let the initial value of k be 1.
4) Setting time constants T1 and T2, wherein T1 represents the time when the imaging device on the mobile platform finishes embryo image shooting; and triggering the embryo detection microfluidic chip to detect each substance to be detected (physiological and biochemical indexes) after the time T1 is reached. T2 represents the time when the device completes embryo image shooting and metabolite detection, and after the T2 time is reached, the embryo detection system enters the next cycle to perform image shooting and physiological and biochemical detection on the embryo again.
5) And setting the heating temperature of the heating plate below the embryo detection microfluidic chip so as to control the culture solution in the embryo detection microfluidic chip to be in a proper temperature range.
6) And starting the gas-liquid mixing unit, and adjusting the opening degree of a valve of the gas input module to enable the pH value and the dissolved oxygen in the culture solution to be within a required range. During gas-liquid mixing, the air inlet and the air outlet of the reservoir are opened, so that gas-liquid is fully mixed.
7) And starting a pumping device of the culture solution, injecting the culture solution into the embryo detection microfluidic chip, and placing the embryo into an embryo culture chamber of the embryo detection microfluidic chip for culture.
8) And the mobile platform resets and stays at the reference position.
9) After the system detects the designated trigger, the mobile platform respectively moves A1，A2Position (2 embryo culture chambers for example), camera was used to capture the embryo growth, the total time spent for this operation T1. After time T1, the metabolite (or other substance to be detected) detection phase is entered.
10) The metabolites (or other substances to be detected) are detected in different detection chambers respectively. Initiating for detecting CkA detection liquid delivery pump for physiological index substances, wherein the detection liquid delivery pump sequentially injects detection liquid into the embryo detection microfluidic chip, enzyme in the detection liquid is fixed on an electrode, after the fixation, the culture liquid delivery pump is started to inject culture liquid into the embryo detection microfluidic chip, the cultured culture liquid is pushed into a detection chamber, current signals in the process of enzyme catalytic reaction are collected by an electrochemical workstation, and thus the change condition of the physiological index of the embryo (taking 2 main detection channels as an example, B is respectively used as B) is observed in real time1，B2. Each main channel needs to detect CkA physiological and biochemical index, at which time B is detected1 C1～k；B2 C1～kAnd (c) a metabolite. ). And finally, discharging the waste liquid in the chip flow channel through a waste liquid outlet.
11) And judging whether the time consumed by embryo image shooting and metabolite detection is more than T2. If T > T2, the detection enters the next loop, and the procedure returns to the flow 9) to be executed again.
According to the embodiment, the micro-fluidic chip and the system for embryo detection can realize gas-liquid mixing in a controllable proportion and constant-temperature storage of biological reagents, and provide feasibility for long-term culture of embryos; the interior of the embryo detection microfluidic chip is completely sealed, so that the interference of the external environment on the detection process can be effectively shielded; the detachable sealing block at the top of the embryo culture chamber greatly facilitates the loading and the taking out of the embryo; the detection chamber is positioned at the downstream of the embryo culture chamber, so that the separation of embryo culture and detection is realized, and noninvasive detection of embryos can be realized; and the micro-environment of the embryo and the culture solution is controlled by the gas-liquid mixing unit, so that the embryo can be controllably cultured on the chip for a long time. In addition, the long-term independent controllable culture of a plurality of embryos can be realized through the simple superposition of the embryo culture chamber, the detection chamber and the related structures thereof, and the long-term noninvasive detection of a plurality of metabolic indexes of the plurality of embryos can be realized; moreover, the combination of delayed photographing analysis and metabolite detection is integrated, and the embryo screening capability can be effectively improved. The method can realize the automatic culture and detection of the embryo, all related instruments are simple and easy to operate, even non-professional personnel can carry out the operation, the operation process is simplified, and researchers can be helped to comprehensively analyze the growth and development conditions of the embryo so as to select the embryo with the strongest activity for transplantation. Therefore, the microfluidic chip and the embryo detection system for embryo detection have important application prospects in embryo culture and screening and single embryo transfer.
The present application has been described in detail with reference to the embodiments, but the present application is not limited to the embodiments described above, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present application. Furthermore, the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
Claims (10)
1. Embryo detection micro-fluidic chip, its characterized in that includes that the flow direction along the culture solution sets gradually:
an embryo culture chamber for culturing an embryo and capable of intercepting the embryo and flowing the culture fluid out of the embryo culture chamber;
the detection chamber is communicated with the embryo culture chamber and is used for accommodating the culture solution flowing out of the embryo culture chamber and detecting the culture solution.
2. The embryo detection microfluidic chip according to claim 1, wherein the embryo culture chamber is provided with a first liquid outlet, the embryo culture chamber is in communication with the detection chamber through the first liquid outlet, and the first liquid outlet is sized to intercept the embryo and allow the culture liquid to flow out of the embryo culture chamber.
3. The microfluidic chip for embryo detection according to claim 1, wherein the embryo culture chamber is provided with an opening, and the opening is sized to allow the embryo to be transferred into and out of the embryo culture chamber through the opening.
4. The microfluidic chip for embryo detection according to claim 3, wherein the microfluidic chip is further provided with a sealing plug for closing and opening the opening.
5. The microfluidic chip for embryo detection according to any one of claims 1 to 4, wherein a backflow prevention part is arranged between the embryo culture chamber and the detection chamber.
6. The microfluidic chip for embryo detection according to any one of claims 1 to 4, wherein the detection chamber is provided with an electrochemical reaction unit comprising a three-electrode system, and the electrochemical reaction unit is used for detecting embryo metabolites in the culture solution.
7. An embryo detection system comprising the embryo detection microfluidic chip of any one of claims 1 to 6.
8. The embryo detection system of claim 7, further comprising an optical detection unit for morphologically detecting an embryo fed into the embryo culture chamber.
9. The embryo detection system according to claim 7, further comprising a gas-liquid mixing unit, wherein the gas-liquid mixing unit is communicated with the embryo culture chamber and is used for supplying culture solution to the embryo culture chamber.
10. The embryo detection system of claim 9, wherein the gas-liquid mixing unit comprises:
the liquid storage device is communicated with the embryo culture chamber and is used for containing the culture solution;
the gas input module is used for introducing gas with preset content into the liquid storage device, and the gas comprises oxygen and carbon dioxide.
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