WO2022257514A1 - Méthode de construction d'un système de biodétection pour la mesure de paramètres physiologiques et pathologiques de puce d'organe - Google Patents

Méthode de construction d'un système de biodétection pour la mesure de paramètres physiologiques et pathologiques de puce d'organe Download PDF

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WO2022257514A1
WO2022257514A1 PCT/CN2022/079828 CN2022079828W WO2022257514A1 WO 2022257514 A1 WO2022257514 A1 WO 2022257514A1 CN 2022079828 W CN2022079828 W CN 2022079828W WO 2022257514 A1 WO2022257514 A1 WO 2022257514A1
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chip
electrode
organ
sensor
cells
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PCT/CN2022/079828
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Chinese (zh)
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裴昊
余紫荆
李丽
万莹
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华东师范大学
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
    • G01N27/3278—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction involving nanosized elements, e.g. nanogaps or nanoparticles

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  • the invention belongs to the technical field of 3D in vitro culture and electrochemical analysis of cells, and relates to a construction method of a biosensing system for detecting physiological and pathological parameters of an organ chip, which integrates an organ chip and a plurality of electrochemical biosensors.
  • Organ chip is a 3D in vitro tissue model that more realistically reflects the human body. During the construction of organ chip, corresponding human cell lines are cultivated in the chip model to simulate the structure and functional units of real human tissues or organs. As an emerging 3D in vitro disease model, organ chips make up for the shortcomings of existing 2D models and animal models, and have great application potential in biological development, drug development and precision medicine.
  • the purpose of the present invention is to provide a method for constructing a biosensing system for detecting the physiological and pathological parameters of the organ chip, which combines the organ chip technology with the electrochemical analysis technology, and connects the design at the outlet of the chip.
  • the organ-on-a-chip analysis platform is easy to construct, has a wide range of applications, and various analysis parameters; combining the organ-on-a-chip with electrochemical sensors, it can monitor the growth microenvironment of the three-dimensional in vitro blood vessel model in real time, and realize the real-time dynamic monitoring of the physiological status of the organ on the chip, which is convenient More accurate and rapid artificial adjustments to increase the success rate of preparing organ chips, more long-term dynamic monitoring of the growth of organ chips, and more real-time and convenient response to drug effects.
  • this integrated chip analysis platform facilitates researchers to more precisely control the microenvironment of chip growth, improve the success rate of organ chip in vitro culture, and more quickly monitor the microenvironment during the growth and development of 3D in vitro tissue models. Changes in clinical testing indicators for early diagnosis of diseases and detection of changes in physiological environment parameters.
  • FIG. 1 The design model of an electrochemical sensing system for monitoring the physiological indicators of the organ chip constructed by the present invention is shown in Figure 1, wherein the master plates of each layer of the blood vessel chip model are shown in Figure 2, and the single-layer detail diagram is shown in Figure 3 .
  • inject fibroblasts and human umbilical vein endothelial cells into the pre-prepared chip model combine the electrode sensor with the PDMS electrode chip with a liquid storage hole to obtain the electrode sensor chip; connect the organ chip and the electrode sensor chip in series , monitor five physiological environment parameters including pH, ATP, ROS, cholesterol and oxygen content in the metabolic solution of the chip.
  • the present invention provides a biosensing system for detecting physiological and pathological parameters of organ chips, said system comprising: organ chips, pH sensor chips, ROS sensor chips, ATP sensor chips, oxygen content sensor chips , Cholesterol sensor chip.
  • the organ-on-a-chip includes a heart organ-on-a-chip, a kidney organ-on-a-chip, a lung organ-on-a-chip, a brain organ-on-a-chip, a blood vessel organ-on-a-chip, and an intestinal organ-on-a-chip.
  • the invention provides a method for constructing a biosensing system for detecting physiological and pathological parameters of an organ chip, said method comprising the following steps:
  • Step (1) mix the polydimethylsiloxane main agent and the curing agent in a mass ratio of 10:1, and then pour it on the pre-designed chip motherboard for curing, and then combine the cured PDMS template with the master
  • the board is separated;
  • the main agent is Sylgard 184 polymer, and the curing agent is Sylgard 184 curing agent;
  • Step (2) bonding the PDMS template prepared in step (1) to obtain an organ chip
  • Step (3) injecting the cell mixture into the organ chip obtained in the above step (2), and culturing in a constant temperature incubator;
  • Step (4) modifying the electrochemical sensors that detect different parameters on the glass sheet
  • Step (5) mix the polydimethylsiloxane main agent and the curing agent in a mass ratio of 10:1, and then pour it on the pre-designed electrode chip motherboard for curing, and combine the PDMS template obtained after curing with the obtained
  • the electrode chip motherboard is separated;
  • the main agent is Sylgard 184 polymer, and the curing agent is Sylgard 184 curing agent;
  • Step (6) bonding the PDMS template prepared in step (5) on the glass sheet of the modified electrode sensor in the step (3) to obtain an electrode sensor chip;
  • Step (7) connecting the inlets of each electrode sensor chip in step (6) in series with the outlet of the organ chip in step (3) to form a liquid circulation pipeline, and the liquid in the blood vessel chip flows through the electrode chip through a peristaltic pump, Thus, a biosensing system for detecting physiological and pathological parameters of the organ chip is obtained.
  • step (1) the chip motherboard is divided into a cell culture layer and a culture medium layer;
  • the size of the main channel of the cell culture layer of the mother chip is 500-1000 ⁇ m in width and 100-200 ⁇ m in height; preferably, the size of the main channel is 500 ⁇ m in width and 200 ⁇ m in height.
  • the size of the branch channel of the cell culture layer of the motherboard chip is 200-250 ⁇ m in width and 400-500 ⁇ m in height; preferably, the size of the branch channel is 200 ⁇ m in width and 500 ⁇ m in height.
  • the size of the culture medium layer of the chip mother board is 17 mm in length, 7 mm in width, and 500-700 ⁇ m in height; preferably, it is 17 mm in length, 7 mm in width, and 500 ⁇ m in height.
  • the inlets and outlets of the chip motherboard are circular holes with a diameter of 200-500 ⁇ m; preferably, 500 ⁇ m.
  • the curing temperature is 60-80°C; preferably, 60°C.
  • the curing time ranges from 2 to 4 hours; preferably, it is 2 hours.
  • step (2) the number of bonded PDMS templates is 3.
  • the organ chip comprises medium outlet layer PDMS, PDMS porous membrane, cell culture layer PDMS, PDMS porous membrane, medium inlet layer PDMS; the order is the first layer of medium outlet layer PDMS, the second Two layers of PDMS porous membrane, the third layer of cell culture layer PDMS, the fourth layer of PDMS porous membrane, the fifth layer of medium inlet layer PDMS.
  • the bonding content is the PDMS template of the medium outlet layer, the PDMS porous membrane, the PDMS template of the cell culture layer, the PDMS porous membrane, and the PDMS template of the medium inlet layer.
  • the bonding conditions are that the radio frequency power is 400-600w, the processing time is 20-40s, and the oxygen flow rate is 50-400mL/min; preferably, the radio frequency power is 600w, the time is 40s, and the oxygen flow rate is 200mL/min. min;
  • the cell mixture is a cell mixture of fibroblasts and human umbilical vein endothelial cells, a cell mixture of human umbilical vessel endothelial cells and cardiomyocytes derived from human induced pluripotent stem cells;
  • the density of the human umbilical vein endothelial cells, fibroblasts, human umbilical vessel endothelial cells and human induced pluripotent stem cell-derived cardiomyocytes is 2 ⁇ (10 6 -10 7 ) cells/mL; preferably, 2 ⁇ 10 6 cells/mL.
  • the number ratio of the fibroblasts and the human umbilical vein endothelial cells is 1:1-1:5; preferably, it is 1:1.
  • the number ratio of the human umbilical vascular endothelial cells and the cardiomyocytes derived from human induced pluripotent stem cells is 1:1-1:3; preferably, it is 1:1.
  • step (3) the two kinds of cells are mixed in a matrigel solution with a concentration of 3-10 mg/mL; preferably, 5 mg/mL or 10 mg/mL.
  • the matrigel solution includes but not limited to matrigel, bovine fibrinogen solution, type I collagen, preferably, matrigel or type I collagen.
  • the fibroblasts and human umbilical vein endothelial cells are mixed in an 8-10 mg/mL matrigel solution; the matrigel solution includes matrigel, bovine fibrinogen solution, and type I collagen.
  • the human umbilical vessel endothelial cells and cardiomyocytes are mixed in a 3-10 mg/mL collagen solution;
  • the collagen solution includes matrigel, bovine fibrinogen solution, and type I collagen.
  • step (3) the culture condition of the cell mixture is: 37° C., 5% CO 2 .
  • the electrode sensor includes: pH electrode sensor, ROS electrode sensor, oxygen content electrode sensor, cholesterol electrode sensor, ATP electrode sensor;
  • the pH electrode sensor uses the carbon electrode modified polyaniline as the working electrode, the carbon electrode as the counter electrode, and Ag/AgCl as the reference electrode; by measuring the relationship between the potential difference between the working electrode and the reference electrode and the pH Calculate the pH of the solution.
  • the pH electrode sensor is a commercially prepared electrode purchased from Qingdao Wave Carbon Technology Co., Ltd.
  • the ROS electrode sensor uses a gold electrode modified with horseradish peroxidase as a working electrode, platinum as a counter electrode, and Ag/AgCl as a reference electrode; the ratio between the ROS concentration and the peak current is measured by cyclic voltammetry. Relationship to calculate the concentration of ROS in the solution to be tested.
  • the preparation method of the ROS electrode sensor is as follows: 1) Platinum nanoparticles and gold nanoparticles are respectively deposited on the pre-cleaned glass substrate, and the areas are successively 1mm ⁇ 3mm and 1mm ⁇ 1mm; 2) 0.5 ⁇ L horseradish The catalase polymer solution was added dropwise on the surface of the gold electrode, and placed in the dark overnight at 4°C. 3) Coating Ag/AgCl paste on the glass substrate.
  • the oxygen content electrode sensor uses platinum as the working electrode and the counter electrode, and Ag/AgCl as the reference electrode; the oxygen content in the solution to be measured is calculated by using the relationship between the oxygen content and the ampere current.
  • the preparation method of the oxygen content electrode sensor is as follows: 1) depositing platinum nanoparticles on a pre-cleaned glass substrate, and 2) coating Ag/AgCl paste on the glass substrate.
  • the cholesterol electrode sensor uses a gold electrode modified with horseradish peroxidase and cholesterol oxidase by DNA origami as a working electrode, platinum as a counter electrode, and Ag/AgCl as a reference electrode; Utilize cyclic voltammetry to measure cholesterol The relationship between concentration and peak current to calculate the concentration of cholesterol in the solution to be tested.
  • the preparation method of the cholesterol electrode sensor is as follows: 1) depositing gold nanoparticles on the pre-cleaned glass substrate; 2) dripping the peroxidase solution on the surface of the gold electrode, and drying naturally to obtain HOD/Au; 3) Add cholesterol oxidase dropwise on the surface of 1), and let it dry naturally to obtain a COD/HOD/Au electrode. 4) Deposit platinum nanoparticles and coat Ag/AgCl paste on the glass substrate.
  • the ATP electrode sensor uses a gold electrode modified with an ATP probe as a working electrode, platinum as a counter electrode, and Ag/AgCl as a reference electrode, and uses cyclic voltammetry to measure the relationship between the ATP concentration and the peak current. Calculate the ATP concentration in the solution to be tested.
  • the preparation method of the ATP electrode sensor is as follows: 1) depositing gold nanoparticles on a pre-washed glass substrate; 2) adding a DNA aptamer with a sulfhydryl group at the 3' end dropwise on the surface of the gold electrode, and incubating for 16 hours ; 3) Soak in 1 mol/L NaClO 4 containing 0.1 mol/L 2-mercaptoethanol for 10 min; 4) Rinse with 10 mol/L HEPES containing 50 mol/L NaClO 4 . 5) Deposit platinum nanoparticles and coat Ag/AgCl paste on the glass substrate.
  • the curing temperature is 60-80°C; preferably, 60°C.
  • the curing time ranges from 2 to 4 hours; preferably, it is 2 hours.
  • the flow channel of the electrode chip motherboard has a width of 500-1000 ⁇ m and a height of 200-500 ⁇ m; preferably, a width of 500 ⁇ m and a height of 500 ⁇ m.
  • the diameter of the hole on the electrode chip motherboard is 800-1000 ⁇ m, and the height is 500-1000 ⁇ m; preferably, the diameter of the hole is 800 ⁇ m, and the height is 500 ⁇ m.
  • the plasma bonding conditions are: radio frequency power 400-600w, time 20-40s, oxygen flow rate 50-200mL/min.
  • the radio frequency power is 600w
  • the time is 40s
  • the oxygen flow rate is 200mL/min.
  • step (7) the rotating speed of the peristaltic pump is 3rpm/min, and the transmission material of the peristaltic pump is: a 1:1 mixture of fibroblast culture medium and human umbilical vein endothelial cell culture medium or human umbilical vessel endothelial cell culture medium 1:1 mixture with cardiomyocyte culture medium;
  • the fibroblast culture medium is FGM-2;
  • the human umbilical vein endothelial cell culture medium is EGM-2;
  • the human umbilical vessel endothelial cell culture medium is EGM;
  • the cardiomyocyte culture medium is CCM.
  • the present invention also provides a biosensor system for monitoring organ-on-a-chip physiological and pathological indicators constructed by the above-mentioned method, and the system includes: organ-on-a-chip, pH, ATP, ROS, oxygen content and cholesterol sensor chips.
  • the method for constructing the biosensing system provided by the present invention can obtain a 3D artificial blood vessel model in vitro, and monitor the growth status of the organ chip dynamically in real time through an electrochemical sensor.
  • the biosensing system provided by the invention can realize automatic analysis, simplify manual operation, and reduce experimental error and experimental cost.
  • the monitoring objects of the biosensing system provided by the present invention include, but are not limited to, blood vessel organ-on-a-chip, heart organ-on-a-chip, kidney organ-on-a-chip, lung organ-on-a-chip, brain organ-on-a-chip, and intestinal organ-on-a-chip.
  • the present invention also provides the application of the above-mentioned biosensing system in monitoring the physiological state of the organ chip, disease process, simulating disease, drug efficacy testing process and predicting human drug response.
  • the present invention also provides a method of using the above-mentioned biosensor system, the method comprising the following steps:
  • Step 1 Inject the mixed cell liquid into the culture layer in the chip model for culturing; the chip outlet is connected to five electrode chip inlets; and the dynamic monitoring of the system is realized through a peristaltic pump.
  • Step 2 monitoring the electrochemical signal of each electrode chip
  • Step 3 According to the electrochemical signal, judge whether the microenvironment of cell growth in the chip is normal, such as: pH, oxygen content, cholesterol, etc.; judge whether the cells are subjected to external stimuli and cause stress reactions such as: ROS, ATP, etc.
  • the cells are fibroblasts, human umbilical vein endothelial cells, human umbilical vessel endothelial cells and cardiomyocytes derived from human induced pluripotent stem cells.
  • the density of human umbilical vein endothelial cells, fibroblasts, human umbilical vessel endothelial cells and cardiomyocytes is 2 ⁇ (10 6 -10 7 ) cells/mL; preferably, 2 ⁇ 10 6 cells/mL.
  • the number ratio of the fibroblasts and the human umbilical vein endothelial cells is 1:1-1:5; preferably, it is 1:1.
  • the number ratio of the human umbilical vascular endothelial cells and the cardiomyocytes derived from human induced pluripotent stem cells is 1:1-1:3; preferably, it is 1:1.
  • Described human umbilical vein endothelial cells and fibroblasts are mixed in matrigel solution, and the concentration of described matrigel solution is 8-10mg/mL; Preferably, is 10mg/mL; Described matrigel solution comprises matrigel, bovine Fibrinogen solution, type I collagen, etc.
  • the human umbilical vessel endothelial cells and cardiomyocytes are mixed in a 3-10 mg/mL collagen solution; the collagen solution includes Matrigel, bovine fibrinogen solution, type I collagen, etc.; preferably, 5 mg/mL of I type collagen.
  • step 1 the culture condition of the organ chip is: 37° C., 5% CO 2 .
  • the cell culture medium in the culture layer is an equal mixture of fibroblast culture medium FGM-2 and human umbilical vein endothelial cell culture medium EGM-2 or cardiomyocyte culture medium CCM and human umbilical vein endothelial cell culture medium An equal mixture of EGM.
  • step 1 the speed of the peristaltic pump is 3rpm/min.
  • the electrochemical signals monitored are: the pH sensor measures the potential difference, the oxygen content sensor measures the peak current in cyclic voltammetry, the ROS sensor measures the peak current in cyclic voltammetry, and the ATP sensor measures the peak value in cyclic voltammetry Current, the cholesterol sensor measures the peak current in cyclic voltammetry.
  • the beneficial effects of the present invention include: in the present invention, human umbilical vein endothelial cells and fibroblasts and/or human umbilical vessel endothelial cells and cardiomyocytes are mixed and cultured in a chip model to obtain an organ chip, and the organ chip is combined with a plurality of electrochemical sensors
  • a chip analysis platform is integrated to realize real-time dynamic monitoring of the growth status of the 3D in vitro model and the physiological microenvironment, reduce research costs and speed up research, and can also provide new monitoring parameters and detection methods for clinical sample analysis.
  • Fig. 1 is the schematic diagram of the blood vessel chip model proposed by the present invention
  • Fig. 2 is a schematic diagram of each layer of the motherboard of the blood vessel chip proposed by the present invention.
  • Fig. 3 is a detailed view of a single layer of the blood vessel chip proposed by the present invention.
  • Fig. 4 is a schematic diagram of a pH sensing electrode in the present invention.
  • Fig. 5 is a schematic diagram of the ATP sensing electrode in the present invention.
  • Fig. 6 is a schematic diagram of a ROS sensing electrode in the present invention.
  • Fig. 7 is a schematic diagram of a cholesterol sensing electrode in the present invention.
  • Fig. 8 is a schematic diagram of an oxygen content sensing electrode in the present invention.
  • Fig. 9 is a schematic diagram of a biosensing system.
  • Fig. 10 is a physical diagram of the blood vessel chip.
  • Figure 11 is a physical diagram of the biosensing system.
  • Fig. 12 is a physical diagram of the ATP sensor chip.
  • Fig. 13 is a physical diagram of the oxygen content sensing chip.
  • Figure 14 is a physical diagram of the ROS sensor chip.
  • Fig. 15 is a physical diagram of a cholesterol sensing chip.
  • Fig. 16 is a physical diagram of the pH sensor chip.
  • step (3) The three PDMS templates prepared in step (1) were bonded layer by layer through a plasma cleaner to obtain a blood vessel chip model.
  • the bonding conditions were: RF power 600w, time 40s, oxygen flow rate 200mL/min.
  • the electrode for electrochemical sensing of pH is a commercially prepared electrode, purchased from Qingdao Wave Carbon Technology Co., Ltd.
  • the formed pH sensor chip is shown in FIG. 16 .
  • (11) Mix the polydimethylsiloxane main agent and the curing agent evenly at a mass ratio of 10:1, and after removing air bubbles in a vacuum, pour it on the pre-designed electrode chip motherboard, and cure the obtained product after two hours of curing.
  • the PDMS template is separated from the electrode chip motherboard; the main agent is Sylgard 184 polymer, and the curing agent is Sylgard 184 curing agent.
  • the electrode sensor includes: pH electrode sensor, ROS electrode sensor, oxygen content electrode sensor, cholesterol electrode sensor, ATP electrode sensor;
  • Step (14) Plasma bond the PDMS template prepared in step (13) with the electrode sensor glass sheet to obtain an electrode sensor chip; the bonding conditions are: RF power 600w, time 40s, oxygen flow rate 200mL/min.
  • the peristaltic pump continuously feeds the 1:1 mixture of endothelial cell culture medium and fibroblast culture medium to the vascular organ chip at a speed of 3 rpm/min.
  • step (2) Perforate the inlet and outlet of the PDMS template obtained in step (1), wherein the media outlet and inlet layers each have six 500 ⁇ m round holes, and the cell culture layer has three 500 ⁇ m round holes.
  • step (3) The three PDMS templates prepared in step (1) were bonded layer by layer through a plasma cleaner to obtain a blood vessel chip model.
  • the bonding conditions were: RF power 600w, time 40s, oxygen flow rate 200mL/min.
  • step (4) The heart-vascular chip containing cells obtained in step (4) was cultured at 37° C. under 5% CO 2 .
  • the electrode for electrochemical sensing of pH is a commercially prepared electrode, purchased from Qingdao Wave Carbon Technology Co., Ltd.
  • the formed pH sensor chip is shown in FIG. 16 .
  • (11) Mix the polydimethylsiloxane main agent and the curing agent evenly at a mass ratio of 10:1, and after removing air bubbles in a vacuum, pour it on the pre-designed electrode chip motherboard, and cure the obtained product after two hours of curing.
  • the PDMS template is separated from the electrode chip motherboard; the main agent is Sylgard 184 polymer, and the curing agent is Sylgard 184 curing agent.
  • the electrode sensor includes: pH electrode sensor, ROS electrode sensor, oxygen content electrode sensor, cholesterol electrode sensor, ATP electrode sensor;
  • Step (14) Plasma bond the PDMS template prepared in step (13) with the electrode sensor glass sheet to obtain an electrode sensor chip; the bonding conditions are: RF power 600w, time 40s, oxygen flow rate 200mL/min.
  • the peristaltic pump continuously feeds the 1:1 mixture of endothelial cell culture medium EGM and cardiomyocyte culture medium CCM to the heart-vascular organ chip at a speed of 3 rpm/min.

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Abstract

Méthode de construction d'un système de biodétection pour la mesure de paramètres physiologiques et pathologiques d'une puce d'organe, comprenant les étapes suivantes consistant : à injecter une solution mélangée de cellules dans un modèle de puce pré-conçu, et à à effectuer une culture en continu afin de former la puce d'organe ; puis à connecter une puce de détection électrochimique dans laquelle une conduite de régulation à micro-écoulement est conçue et une sortie de la puce d'organe afin de surveiller plus particulièrement la teneur en oxygène, ATP, pH, ROS et le cholestérol dans des métabolites de la puce d'organe. La méthode de construction est simple et pratique, large dans sa plage d'applications, et diversifiée dans ses paramètres d'analyse ; la puce d'organe est combinée avec un capteur électrochimique, de telle sorte que le micro-environnement de croissance d'un vaisseau sanguin/modèle cardiaque tridimensionnel in vitro peut être surveillé dynamiquement en temps réel ; l'état de santé de culture de modèle peut être ajusté en temps réel, de telle sorte que l'état de santé de culture de modèle est plus conforme à un état de corps vivant réel ; et le système de biodétection peut être utilisé pour explorer le changement d'état physiologique dans un processus de maladie et peut également être utilisé pour une surveillance en ligne de la réponse de la puce d'organe à des médicaments.
PCT/CN2022/079828 2021-06-09 2022-03-09 Méthode de construction d'un système de biodétection pour la mesure de paramètres physiologiques et pathologiques de puce d'organe WO2022257514A1 (fr)

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