CN113046242A - Chip and method for similar in vivo heart organ - Google Patents
Chip and method for similar in vivo heart organ Download PDFInfo
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- CN113046242A CN113046242A CN202110309721.0A CN202110309721A CN113046242A CN 113046242 A CN113046242 A CN 113046242A CN 202110309721 A CN202110309721 A CN 202110309721A CN 113046242 A CN113046242 A CN 113046242A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/10—Perfusion
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
- C12M35/02—Electrical or electromagnetic means, e.g. for electroporation or for cell fusion
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
- C12M35/04—Mechanical means, e.g. sonic waves, stretching forces, pressure or shear stimuli
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
Abstract
The invention discloses an in-vivo heart organ-like chip and a method, comprising a substrate device and a culture solution perfusion device, wherein the surface of the substrate device is provided with a PDMS film, and the top of the PDMS film is provided with the culture solution perfusion device to simulate the condition of blood flow; the substrate device comprises a substrate, wherein a PDMS (polydimethylsiloxane) mold is arranged on the surface of the substrate and is provided with a micro-air channel; the PDMS film comprises a suspended film, and the suspended film is provided with a strain sensing part, an induction electrode and a stimulation electrode.
Description
Technical Field
The invention belongs to the technical field of micro-electromechanical engineering and biomedicine, and particularly relates to an in-vivo heart organ-like chip and a method.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Cardiac dysfunction-induced cardiovascular deaths account for 33% of the total deaths worldwide, accounting for the top of deaths worldwide.
At present, the existing micro-nano sensing devices for detecting myocardial contraction force (or stress) comprise the following parts:
electrical impedance method (Electrical impedance) is proposed by Gievar et al, which plants cardiomyocytes on an interdigitated microelectrode array chip, and the cells cause the distance between the bottom of the cells and the upper surface of the electrodes to change during the beating process, thereby obtaining the change of impedance (resistance and capacitance), but ignores that the generation of the contractile force of the cardiomyocytes is not only related to the contraction displacement.
The Micro-cantilever method (Micro-cantilever) can detect the deflection change caused by myocardial contraction by laser beams, and realizes the measurement of myocardial cell contraction by taking force or stress as direct physical quantity. Such devices require the integration of a laser beam on the back side of the cantilever beam, which can potentially affect the normal metabolic processes of the cell due to heat build-up.
Cell drum (Cell drum) is also a micro-nano device for detecting myocardial contraction behavior. The silicon-based flexible film is prepared based on an MEMS (micro electro mechanical system) process, and meanwhile, the laser and the pressure sensor are integrally packaged. One drawback of this approach is that the interior of the chamber is difficult to package into a closed space, resulting in a signal-to-noise ratio of the acquired signal of less than 3.
The microcolumn array (Micropost array) and the Traction force microscope (Traction force microscope) technology separate the change of displacement through an image algorithm to realize the detection of the shrinkage stress. Both techniques are commonly used for the testing of individual cardiomyocytes. However, the heart is not isolated from myocardial cells, and the internal cell communication mechanism coordinates the same beating of the heart. Both methods require improvement in simultaneous detection of multiple cells.
Based on the above analysis, there is an urgent need to construct a heart organ chip that integrates multiple cell cultures, is close to the in vivo myocardial function, and has the functions of monitoring action potential and contraction simultaneously.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide an organ chip similar to the heart of a human body and a method thereof, wherein the organ chip can be close to the living microenvironment of the heart muscle of the human body, can simultaneously monitor the contraction behavior and the electrophysiological behavior and integrates electrical stimulation and mechanical stimulation into a whole.
In order to achieve the purpose, the invention is realized by the following technical scheme:
in a first aspect, an embodiment of the present invention provides an in-vivo cardiac organ chip, including a substrate device, and a culture perfusion device, wherein a PDMS film is disposed on a surface of the substrate device, and the culture perfusion device is disposed on a top of the PDMS film to simulate a blood flow condition;
the substrate device comprises a substrate, wherein a PDMS (polydimethylsiloxane) mold is arranged on the surface of the substrate and is provided with a micro-air channel;
the PDMS film comprises a suspended film, and the suspended film is provided with a strain sensing part, an induction electrode and a stimulation electrode.
As a further technical scheme, the micro-air channel comprises a plurality of tubular channels and a plurality of columnar channels, the tubular channels and the columnar channels are sequentially and alternately arranged, and adjacent tubular channels and columnar channels are communicated.
As a further technical scheme, one end of the micro air channel is provided with an air inlet, and one end of the micro air channel, which is provided with the air inlet, is inserted into the hose.
As a further technical scheme, the suspended film is attached to the surface of the substrate device.
As a further technical solution, the strain sensing component employs a piezoresistive sensor, and the piezoresistive sensor is formed by CNT and PDMS.
As a further technical scheme, the induction electrodes and the stimulation electrodes are arranged on two sides of the suspended film at intervals of a set distance, and the induction electrodes and the stimulation electrodes are symmetrically arranged in pairs.
As a further technical scheme, the culture solution perfusion device comprises a plurality of channels for transporting nutrient solution and a plurality of cylindrical cell culture devices, the plurality of cylindrical cell culture devices are communicated with the channels, and the channels are provided with liquid inlets and liquid outlets.
In a second aspect, an embodiment of the present invention further provides a method for preparing an in vivo-like cardiac organ chip as described above, including the following steps:
preparing a substrate device containing micro-air channels: spin-coating a layer of SU-8 negative photoresist on the silicon wafer treated by the oxygen plasma, and drying and cooling the silicon wafer to room temperature in vacuum; contacting a mask plate which contains channels and is provided with round holes at equal intervals with a coated silicon wafer and carrying out ultraviolet exposure; performing heat treatment by heating the exposed wafer; dipping the exposed silicon wafer in a developing solution, rinsing with water and drying in the air to develop a micro-channel and a cylinder; coating PDMS on the developed silicon wafer, and stripping after curing to obtain a PDMS mold; sealing the PDMS mold with the substrate quartz glass by a plasma bonding technology;
preparing a PDMS film: a layer of PDMS film is spin-coated on the acrylic plate, stripped after being cured and attached to the surface of the substrate device containing the micro-air channel to form a suspended film; fully stirring CNT and PDMS, coating the uncured CNT-PDMS blend on the surface of the suspended film by a screen printing method, and baking for a set time to form a piezoresistive sensor for sensing deformation;
preparation of a culture solution perfusion device: the channel for transporting the nutrient solution and the cylindrical cell culture device are formed by pouring PDMS into an aluminum mould and then solidifying the PDMS.
As a further technical scheme, a hole is formed in one end of the channel, and a hose is inserted.
As a further technical scheme, an induction electrode and a stimulation electrode are symmetrically prepared at a set distance from a suspended film through screen printing; and mechanically stimulating the in vivo heart organ-like chip and combining with the periodic stimulation of pulse rectangular electrical stimulation.
The beneficial effects of the above-mentioned embodiment of the present invention are as follows:
according to the organ chip, the micro-air channel arranged on the PDMS mold of the substrate device can penetrate through air, so that mechanical stimulation is realized; the culture solution perfusion device can realize co-culture of various cells, the PDMS film can realize simultaneous measurement of myocardial contraction stress and electrophysiology, and electrical stimulation can be carried out through the arrangement of the stimulation electrode; the chip of the invention can be close to the living microenvironment of the heart muscle in the body, can monitor the contraction behavior and the electrophysiological behavior simultaneously, and integrates the electrical stimulation and the mechanical stimulation into a whole, thereby realizing the research on the heart organ chip.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a schematic diagram of an organ chip according to one or more embodiments of the present invention;
FIG. 2 is a flow diagram illustrating the preparation of a substrate device according to one or more embodiments of the present invention;
in the figure: the mutual spacing or size is exaggerated to show the position of each part, and the schematic diagram is only used for illustration;
the device comprises a substrate device 1, a PDMS film 2, a culture solution perfusion device 3, a substrate 4, a PDMS mold 5, a micro-air channel 6, a tubular channel 7, a columnar channel 8, an air inlet 9, a suspended film 10, an induction electrode 11, a strain sensing component 12, a stimulation electrode 13, a channel 14 and a columnar cell culture device 15.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an", and/or "the" are intended to include the plural forms as well, unless the invention expressly state otherwise, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof;
for convenience of description, the words "up", "down", "left" and "right" in the present invention, if any, merely indicate correspondence with the directions of up, down, left and right of the drawings themselves, and do not limit the structure, but merely facilitate the description of the invention and simplify the description, rather than indicate or imply that the device or element referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore should not be construed as limiting the invention.
The terms "mounted", "connected", "fixed", and the like in the present invention should be understood broadly, and for example, the terms "mounted", "connected", "fixed", and the like may be fixedly connected, detachably connected, or integrated; the two components can be connected mechanically or electrically, directly or indirectly through an intermediate medium, or connected internally or in an interaction relationship, and the terms used in the present invention should be understood as having specific meanings to those skilled in the art.
As described in the background, the prior art is deficient, and the present invention provides an on-body heart organ chip and method for solving the above technical problems.
In an exemplary embodiment of the present invention, as shown in fig. 1, an in vivo cardiac organ chip of the kind that can be placed in close proximity to the in vivo cardiac muscle survival microenvironment and can simultaneously monitor contractile behavior, electrophysiological behavior, integrated electrical stimulation and mechanical stimulation.
The organ chip is mainly prepared based on a flexible and transparent PDMS material and mainly comprises three parts: a substrate device 1 containing micro-air channels, a PDMS film 2 which can be embedded with CNT, and a culture solution perfusion device 3.
The substrate device 1 integrates mechanical stimulation, the culture solution perfusion device 3 can realize co-culture of various cells, and the PDMS film 2 can realize simultaneous measurement of myocardial contraction stress and electrophysiology and electrical stimulation thereof.
The surface of the substrate device 1 is provided with a PDMS film 2, and the top of the PDMS film 2 is provided with a culture solution perfusion device 3 to simulate the condition of blood flow.
Specifically, the substrate device 1 includes a substrate 4, a PDMS mold 5 is disposed on a surface of the substrate 4, and a micro-air channel 6 is disposed inside the PDMS mold 5 and used for communicating air to realize mechanical stimulation.
In this embodiment, the substrate 4 may be made of quartz glass.
The micro-air channel 6 comprises a plurality of tubular channels 7 and a plurality of columnar channels 8, the tubular channels 7 and the columnar channels 8 are sequentially and alternately arranged, the adjacent tubular channels and the columnar channels are communicated, one end of the micro-air channel is provided with an air inlet 9, the air inlet of the micro-air channel is communicated with an air source, and air is injected into the micro-air channel to perform mechanical stimulation.
In a further scheme, one end of the micro-air channel can be inserted into a Teflon hose with a corresponding size, and air is input from the Teflon hose inwards.
Specifically, the PDMS film 2 includes a suspended film 10, and the suspended film 10 is provided with a strain sensing component 12, an induction electrode 11 and a stimulation electrode 13;
wherein, the suspended film 10 is attached to the surface of the substrate device.
The strain sensing part 12 is a piezoresistive sensor formed of CNT and PDMS.
The induction electrodes 11 and the stimulation electrodes 13 are arranged on two sides of the suspended film at intervals of a set distance, and the induction electrodes and the stimulation electrodes are symmetrically arranged in pairs.
In this embodiment, the sensing electrodes and the stimulating electrodes are arranged at a position 2mm away from the suspended film, the number of the sensing electrodes is 4, and the number of the stimulating electrodes is 2. Wherein the induction electrode is strip-shaped, the width of the induction electrode is 100 mu m, and the length of the induction electrode is 1 mm; the stimulating electrode is circular and has a diameter of 500 μm.
Specifically, the culture solution perfusion device 3 comprises a channel 14 for transporting nutrient solution and a cylindrical cell culture device 15.
Wherein, a plurality of cylindrical cell culture devices 15 are arranged, the cylindrical cell culture devices are cylindrical, the plurality of cylindrical cell culture devices are all communicated with the channel 14, and the channel is provided with a liquid inlet and a liquid outlet; providing a cell culture solution into the cylindrical cell culture device from a liquid inlet of the channel, and performing cell culture solution perfusion; the liquid outlets of the channels are connected with the liquid conveying pipe in a converging way and used for discharging the metabolic products.
The channel 14 and the cylindrical cell culture device 15 are both made of PDMS by pouring into an aluminum mold and curing, and the aluminum mold is prepared by milling.
The preparation process of the in-vivo heart organ-like chip mainly comprises four parts of substrate device preparation, PDMS film preparation, culture solution perfusion device preparation and mechanical and electrical coupling stimulation realization.
The method specifically comprises the following steps:
(1) preparing a substrate device containing micro-air channels:
firstly, spin-coating a layer of SU-8(3005) negative photoresist with the thickness of 70 μm on a silicon wafer treated by oxygen plasma at 1500r/min, drying the photoresist in vacuum at 140 ℃ for 30 minutes and then cooling the photoresist to room temperature;
then, contacting a mask plate which contains a channel with the width of 100 mu m and the length of 76mm and is provided with round holes with the diameter of 5mm at equal intervals with a coated silicon wafer and carrying out ultraviolet exposure;
then, heat treatment was performed by heat-exposing the wafer at 140 ℃ for 10 minutes; immersing the exposed silicon wafer in a developing solution for 10 minutes, rinsing with water and drying in the air to develop a microchannel and a cylinder;
coating PDMS (according to the mass ratio of 10: 1) on a developed silicon wafer, curing the silicon wafer in an oven at the temperature of 60 ℃, and carefully stripping the silicon wafer to obtain a PDMS mold;
subsequently, the PDMS mold was sealed to the base quartz glass by plasma bonding technique.
In order to realize the pneumatic mechanical stimulation of the micro-channel, a hole can be punched at one end of the channel, and a Teflon hose with a corresponding size is inserted.
The specific preparation process is shown in figure 2 and comprises the following steps:
A. spin-coating a layer of SU-8 negative photoresist with the thickness of 70 mu m on the surface of the silicon wafer;
B. carrying out ultraviolet exposure treatment;
C. carrying out developing operation;
D. casting and curing;
E. coating PDMS and demoulding;
F. plasma bonding, and sealing the PDMS mold with the substrate;
G. one end of the channel is perforated and a Teflon hose is inserted.
(2) Preparation of CNT-embeddable PDMS films: mainly comprises a strain sensing part, an induction electrode and a stimulation electrode.
Firstly, a PDMS film with the thickness of 25 μm is spin-coated on an acrylic plate at the speed of 2000r/min, carefully peeled off after being cured in an oven at the temperature of 60 ℃, and attached to the surface of a substrate device with a micro-air channel to form a suspended film;
sufficiently stirring 8 wt% of CNT (diameter: 20-30nm, length: 10-30 μm) and PDMS, wherein the weight ratio of the curing agent of PDMS to the prepolymer is 10%; the uncured CNT-PDMS blend was coated on the surface of the thin film by screen printing method and then baked at 65 ℃ for 4h to form piezoresistive sensors with thickness of 20 μm and width of 300 μm for sensing deformation.
Through earlier stage simulation, it is confirmed that when the film is subjected to air pressure, large deformation can be formed in the suspended film area and the edge of the film, and therefore, the electrode for detecting the action potential and the stimulating electrode are prevented from being placed in the area.
4 induction electrodes and 2 electric stimulation electrodes are symmetrically prepared at a position 2mm away from the suspended film through screen printing. Wherein the induction electrode is strip-shaped, the width of the induction electrode is 100 mu m, and the length of the induction electrode is 1 mm; the stimulating electrode is circular and has a diameter of 500 μm.
(3) Preparation of a culture solution perfusion device:
the culture solution perfusion device comprises a nutrient solution conveying channel and a cylindrical cell culture device. The two parts are both formed by pouring PDMS (mass ratio of 10: 1) into an aluminum mould and then curing. The aluminum mold was prepared by a milling process with rectangular parallelepiped-shaped protrusions (height 150 μm, width 1000 μm) for forming channels for transporting nutrient solution and cylindrical protrusions (height 150 μm, diameter 10mm) for forming cylindrical cell culture devices.
(4) Mechanical and electrical coupling stimulation effects:
carrying out mechanical stimulation with 10% of tensile deformation and 1Hz frequency for 7 days, wherein the mechanical stimulation is applied to the PDMS film through a micro-air channel; and the electric stimulation is applied to the stimulation electrode in combination with the periodic stimulation of pulse rectangular electric stimulation with the frequency of 2.5Hz, the field strength of 5V/cm and the period of 10 ms. Stimulation by coupling can be used to explore the effect of mechanical and electrical stimulation coupling on cell function.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An in-vivo heart organ chip is characterized by comprising a substrate device and a culture solution perfusion device, wherein a PDMS film is arranged on the surface of the substrate device, and the culture solution perfusion device is arranged at the top of the PDMS film to simulate the condition of blood flow;
the substrate device comprises a substrate, wherein a PDMS (polydimethylsiloxane) mold is arranged on the surface of the substrate and is provided with a micro-air channel;
the PDMS film comprises a suspended film, and the suspended film is provided with a strain sensing part, an induction electrode and a stimulation electrode.
2. The in-vivo heart-like organ chip according to claim 1, wherein the micro air channels comprise a plurality of tubular channels and a plurality of columnar channels, the tubular channels and the columnar channels are alternately arranged in sequence, and adjacent tubular channels and columnar channels are communicated.
3. The in-vivo-like heart organ chip according to claim 2, wherein an air inlet is provided at one end of the micro air channel, and a hose is inserted at one end of the micro air channel provided with the air inlet.
4. The in vivo-like cardiac organ chip of claim 1, wherein said suspended membrane is attached to a surface of a base device.
5. The in-vivo heart-like organ chip of claim 1, wherein the strain sensing member is a piezoresistive sensor formed of CNT and PDMS.
6. The in-vivo heart-like organ chip as claimed in claim 1, wherein the sensing electrodes and the stimulating electrodes are disposed on both sides of the suspended membrane at a predetermined distance, and the sensing electrodes and the stimulating electrodes are symmetrically disposed in pairs.
7. The in-vivo heart-like organ chip according to claim 1, wherein the culture perfusion device comprises a channel for transporting the nutrient solution and a plurality of cylindrical cell culture devices, the plurality of cylindrical cell culture devices are communicated with the channel, and the channel has a liquid inlet and a liquid outlet.
8. The method for preparing an in vivo-like cardiac organ chip as claimed in any one of claims 1 to 7, comprising the steps of:
preparing a substrate device containing micro-air channels: spin-coating a layer of SU-8 negative photoresist on the silicon wafer treated by the oxygen plasma, and drying and cooling the silicon wafer to room temperature in vacuum; contacting a mask plate which contains channels and is provided with round holes at equal intervals with a coated silicon wafer and carrying out ultraviolet exposure; performing heat treatment by heating the exposed wafer; dipping the exposed silicon wafer in a developing solution, rinsing with water and drying in the air to develop a micro-channel and a cylinder; coating PDMS on the developed silicon wafer, and stripping after curing to obtain a PDMS mold; sealing the PDMS mold with the substrate quartz glass by a plasma bonding technology;
preparing a PDMS film: a layer of PDMS film is spin-coated on the acrylic plate, stripped after being cured and attached to the surface of the substrate device containing the micro-air channel to form a suspended film; fully stirring CNT and PDMS, coating the uncured CNT-PDMS blend on the surface of the suspended film by a screen printing method, and baking for a set time to form a piezoresistive sensor for sensing deformation;
preparation of a culture solution perfusion device: the channel for transporting the nutrient solution and the cylindrical cell culture device are formed by pouring PDMS into an aluminum mould and then solidifying the PDMS.
9. The method of claim 8, wherein a hole is formed at one end of the channel, and a hose is inserted.
10. The manufacturing method as set forth in claim 8, wherein the sensing electrode and the stimulating electrode are symmetrically manufactured by screen printing at a set distance from the flying film; and mechanically stimulating the in vivo heart organ-like chip and combining with the periodic stimulation of pulse rectangular electrical stimulation.
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Cited By (3)
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| CN113717851A (en) * | 2021-07-14 | 2021-11-30 | 西安交通大学 | Tissue chip and preparation method thereof |
| CN114939447A (en) * | 2022-05-22 | 2022-08-26 | 苏州大学 | Integrated chip integrating cell human body culture and cell mechanical characteristic measurement |
| WO2024007530A1 (en) * | 2022-07-04 | 2024-01-11 | 齐鲁工业大学 | Optimization method for preparing intestinal organ chip for exploring hg2+ |
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