CN110331097B - Integrated intestinal multi-mode movement three-dimensional cavity intestinal organ chip and method - Google Patents
Integrated intestinal multi-mode movement three-dimensional cavity intestinal organ chip and method Download PDFInfo
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Abstract
The invention provides an integrated intestinal multi-mode movement three-dimensional cavity intestinal organ chip and a method, wherein the integrated intestinal multi-mode movement three-dimensional cavity intestinal organ chip comprises a cavity porous film for culturing differentiated intestinal epithelial cells, a support film is arranged on the outer side of the cavity porous film, the support film is connected with a gas channel, and the support film is driven to move through the air inlet/outlet of the gas channel, so that the cavity porous film is deformed to simulate tension contraction action; the outer side of the cavity porous film is provided with a cavity provided with a containing area, and a culture solution perfusion area can be provided for the cavity porous film to form a micromechanical environment with axial and circumferential shear stress; the circumference of the porous film of the cavity is embedded with a plurality of closing magnetic tapes, and the closing magnetic tapes can generate a magnetic field along with the electrification of a solenoid which is movably arranged outside the cavity, so that the corresponding position of the porous film of the cavity is radially contracted.
Description
Technical Field
The present disclosure belongs to the technical field of micro-electro-mechanical engineering and biomedicine, and in particular relates to an integrated intestinal multi-mode motion three-dimensional cavity intestinal organ chip and a method.
Background
The statements in this section merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Currently, the screening of novel oral drugs for disease treatment is largely dependent on animal models. Before new drugs enter the market, clinical tests of human beings can be further implemented after efficacy and safety evaluation are carried out through animal models. The drug screening cost based on animal models is high, the time consumption is long, and ethical disputes exist; moreover, more than 95% of the drugs passing the test are not suitable for human beings and even have toxic and side effects on human beings. This result is related to the variability in intestinal cell metabolic capacity, absorption efficiency, and transmembrane permeability among species.
Due to the above problems, attention is increasingly being paid to human ex vivo intestinal cell/tissue/organ models. Products such as intestinal epithelial cell culture systems have been developed in succession, but these early products are quite different from the later developed artificial intestinal organs and in-vivo intestinal organs.
Microfluidic devices (micro-fluidic devices) developed from microelectromechanical systems (MEMS) offer the possibility to simulate the micro-physiological/micro-physical environment of isolated cells/tissues/organs, and further derived Organ-on-a-chips (OOCs) offer the possibility to precisely control a number of parameters, simulate in vitro the behavioural activities, mechanical properties and physiological responses of human single/multiple organs. Based on OOC technology, ingber and other subject groups change micro-fluidic chips simulating lung functions into differential culture of intestinal organs, so that intestinal cell-bacteria symbiotic culture can be realized, and influence of pathogenic bacteria on intestinal morphology can be explored.
To the knowledge of the inventors, these studies have made an important contribution to exploring the realization of in vitro simulated intestinal organ function and drug screening, and the obtained intestinal tract has significant progress in various indexes of morphology and function relative to the Transwell model, but the following disadvantages still exist:
only two-dimensional plane cell culture can be realized, and when the shear stress of the microfluid is simulated, only axial shear stress simulation can be realized; the living intestine is morphologically a three-dimensional cavity structure, and thus lacks the hoop shear stress of the fluid in the cavity.
Only a single pattern of tonic contractions can be simulated, and the multimodal form of movement of the intestine (e.g., segmental radial contractions that play a major role in digestive/absorptive functions and peristaltic waves that propel chyme/medication) cannot be simulated.
Disclosure of Invention
In order to solve the problems, the present disclosure provides an integrated intestinal multi-mode movement three-dimensional cavity intestinal organ chip and a method thereof, which can simulate human intestinal organs in vitro, integrate multiple mechanical parameters, and can differentiate the morphology, intestinal epithelial barrier and digestive function of the intestinal organs closer to the body.
According to some embodiments, the present disclosure employs the following technical solutions:
an integrated intestinal multi-modal motile three-dimensional luminal intestinal organ chip comprising:
the device comprises a cavity porous membrane for culturing differentiated intestinal epithelial cells, wherein a supporting membrane is arranged on the outer side of the cavity porous membrane, the supporting membrane is connected with a gas channel, and the supporting membrane is driven to move through the air inlet/outlet of the gas channel, so that the cavity porous membrane is deformed to simulate tension shrinkage action;
the outer side of the cavity porous film is provided with a cavity provided with a containing area, and a culture solution perfusion area can be provided for the cavity porous film to form a micromechanical environment with axial and circumferential shear stress;
the circumference of the cavity porous film is embedded with a plurality of closing magnetic tapes, and the closing magnetic tapes can generate a magnetic field along with the electrification of a solenoid which is movably arranged outside the cavity, so that the corresponding position of the cavity porous film is radially contracted.
In the design scheme, the porous film of the cavity can generate tension shrinkage action, sectional radial shrinkage action and multi-mode motion simulation of axial and circumferential shear stress through the cooperation of the elements; based on multiple mechanical control parameters, the relationship between the intestinal organ metabolic capacity, absorption efficiency and transmembrane permeability is explored.
Alternatively, a metabolic solution collecting channel is further arranged on the outer side of the cavity porous film to collect metabolic solution of intestinal epithelial cells.
As an alternative embodiment, the cavity porous film is made of flexible polydimethylsiloxane material and has a thickness of 3-5 μm.
Alternatively, the closed magnetic tape is an annular magnetic tape, and is formed by fully mixing magnetic particles with the cavity porous film and then solidifying the magnetic particles, and the magnetic particles are uniformly distributed on the surface of the cavity porous film at intervals.
As an alternative implementation mode, the energizing voltage of the solenoid can be adjusted, the intensity of the voltage is adjusted, the magnetic field intensity is changed, the radial contraction of the magnetic ring belt with different amplitudes is realized, and the simulation of different positions and different states of the intestinal tract is realized by controlling the axial moving position and the moving speed of the solenoid.
As an alternative implementation mode, the gas channels comprise two gas channels, the gas channels are arranged on two sides of the cavity porous film, are made of the same material as the cavity porous film, are bonded and packaged through plasma treatment, and have the same length and thickness as the cavity porous film.
As an alternative embodiment, intestinal epithelial cells can be cultured on the inner side and the outer side of the cavity porous film, the intestinal organ chip is used for marking the designated protein, the morphological characterization of a confocal microscope is performed, and the formation state of small intestinal villi is compared; the extent of intestinal cell gap junction is indirectly reflected by the analysis of the intestinal epithelial barrier function on the inside by recording the transmembrane resistance technique.
The preparation method of the three-dimensional cavity intestinal organ chip comprises the following steps:
preparing a cavity porous film: spin-coating a layer of SU-8 negative photoresist on a silicon wafer, cooling to room temperature after vacuum drying, contacting a photomask with the coated silicon wafer, exposing the wafer by heating, and performing heat treatment, or baking after exposure, the micro-column array is then developed by immersing the silicon wafer in a developing solution for a period of time, rinsing with water and drying in air, the flexible polydimethylsiloxane material is spin-coated on the micro-column array, stripping after curing, attaching a thin film around a Teflon hose for one circle, and realizing close joint by semi-curing the flexible polydimethylsiloxane material;
preparing a micro-gas channel: filling a flexible polydimethylsiloxane material into a mold, and then curing, wherein the mold comprises two parts with the same structure, each part is provided with at least two bulges, the two parts are oppositely arranged, and the fit packaging is realized through plasma treatment;
preparing a closed magnetic tape, and adding Fe 3 O 4 The particles are fully mixed with the flexible polydimethylsiloxane material, then the mixture is spin-coated on an acrylic plate with uniform surface, after curing, the mixture is peeled off, plasma is used for activating the surface of the cavity flexible polydimethylsiloxane material film, and the peeled Fe is removed 3 O 4 The magnetic films are uniformly adhered to the surfaces of the magnetic films at equal intervals;
and (5) finishing the assembly of the prepared three parts through keys and a process.
The working method of the three-dimensional cavity intestinal organ chip comprises the following steps:
driving the supporting film to move through the air inlet/outlet of the air channel, so that the cavity porous film is deformed to simulate and analyze tension shrinkage;
or/and, by changing the flow rate of the nutrient solution, forming a micromechanical environment with axial and circumferential shear stress, and simulating and analyzing the relationship between the flow rate of the liquid and the shear stress;
or/and, by changing the energizing voltage of the solenoid and the moving speed of the solenoid, the radial contraction and peristaltic wave of intestinal tracts are simulated and analyzed.
As an alternative implementation mode, when simulating and analyzing the radial contraction of the intestinal tract section, under the condition that a cavity film with the same rigidity and thickness as those of living intestinal tissues is prepared, establishing a calibration relation between the magnetic field strength and the deformation of the PDMS film by using simulation software, changing the voltage of a solenoid to search the deformation of the cavity film corresponding to the deformation, and realizing the radial contraction of the section on the cavity film according to a set frequency by the solenoid;
when peristaltic waves are simulated and analyzed, the closed magnetic tape is alternately attracted and released, the speed of the peristaltic waves is calculated by using the time difference between the gaps of the magnetic ring belt and the two wave peaks, and the relation between different speeds of the solenoid and the peristaltic wave speed of the cavity is determined.
As an alternative implementation mode, when the tension shrinkage is simulated and analyzed, the two side channels are utilized to realize the deformation of the pneumatic stretching film, and the relationship between different pneumatic pressures and the deformation is determined.
As an alternative implementation mode, when the relation between the liquid flow rate and the shear stress is simulated and analyzed, the internal shaft shear stress under ideal conditions is calculated according to the liquid flow rate in the intestinal tract of the living body, the numerical value is imported into simulation software, and the flow rate of the culture solution required by the cavity intestinal organ chip is simulated reversely.
Compared with the prior art, the beneficial effects of the present disclosure are:
aiming at the defect of lack of a multi-mode movement mode of an in-vivo intestinal tract, the invention provides a three-dimensional cavity intestinal organ chip with multi-movement parameter simulation, which is more similar to the shape, intestinal epithelial barrier and digestion function of a living intestinal organ in vitro; the multi-mode simulation of the tension shrinkage, the segmental radial shrinkage, the peristaltic wave, the circumferential shear stress and the axial shear stress of the intestinal tract can be realized; the effects of multiple mechanical parameters on intestinal morphology and function formation are truly revealed in a bionic state, and the method is helpful for researching intestinal organ chips and the like.
Drawings
The accompanying drawings, which are included to provide a further understanding of the disclosure, illustrate and explain the exemplary embodiments of the disclosure and together with the description serve to explain the disclosure, and do not constitute an undue limitation on the disclosure.
FIG. 1 (a) is a schematic diagram of stress distribution caused by a porous film of the present disclosure at a gas pressure of 10 kPa;
FIG. 1 (b) is a schematic diagram showing the linear relationship between the maximum strain and the air pressure value in the air pressure range of 5kPa to 200 kPa;
FIG. 2 is a flow chart of the preparation of a porous film of the cavity of the present disclosure;
FIG. 3 is a schematic diagram of a three-dimensional cavity long organ chip preparation flow of the present disclosure;
fig. 4 is a schematic structural view of the present disclosure.
The specific embodiment is as follows:
the disclosure is further described below with reference to the drawings and examples.
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present disclosure. 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 disclosure 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 in accordance with the present disclosure. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In the present disclosure, terms such as "upper", "lower", "left", "right", "front", "rear", "vertical", "horizontal", "side", "bottom", and the like indicate an azimuth or a positional relationship based on the azimuth or the positional relationship shown in the drawings, are merely relational terms determined for convenience in describing structural relationships of the various components or elements of the present disclosure, and do not denote any one of the components or elements of the present disclosure, and are not to be construed as limiting the present disclosure.
In the present disclosure, terms such as "fixedly coupled," "connected," and the like are to be construed broadly and refer to either a fixed connection or an integral or removable connection; can be directly connected or indirectly connected through an intermediate medium. The specific meaning of the terms in the disclosure may be determined according to circumstances, and should not be interpreted as limiting the disclosure, for relevant scientific research or a person skilled in the art.
As shown in fig. 4, a three-dimensional cavity intestinal organ chip integrated with intestinal multi-mode motion simulation can be used for morphology differentiation, function formation and colony coexistence research, and comprises seven parts, namely: the device comprises a cavity porous film (1), magnetic endless belts (2) which are distributed at intervals, a movable solenoid (3), a metabolic liquid collecting device (4), a culture liquid perfusion device (5), two side gas channels (6) (7) and a supporting film (8). Wherein the cavity porous film (1) is the core of the whole chip, intestinal epithelial cells can be differentiated by internal and external culture, gas channels (6) (7) are arranged on two sides of the cavity porous film, and the cavity porous film is surrounded by a culture solution perfusion device (5). The annular magnetic tape (2) is embedded on the surface of the cavity porous film (1) and distributed at equal intervals; the movable solenoid (3) can axially move along the cavity porous film (1), and when the movable solenoid is electrified, a magnetic field is generated to enable the movable solenoid to radially shrink.
Specifically, in this embodiment, the matrix material of the porous film of the cavity is selected from flexible Polydimethylsiloxane (PDMS) materials with adjustable rigidity and good biocompatibility, the characteristic dimension of the chip (i.e., the diameter of the porous film) is 2 μm, the thickness of the porous film of the cavity is 3 μm-5 μm, the length of the whole three-dimensional intestinal organ chip is 38mm, the width is 13mm, and the thickness is 1 mm-2 mm.
Of course, in other embodiments, the dimensions described above may be modified and adapted, which are simple alternatives as will be readily apparent to those skilled in the art, and are intended to be within the scope of the present disclosure.
The annular magnetic tape (2) is composed of magnetic particles (such as Fe) with particle diameter of 50-150 nm 3 O 4 ) Fully mixing with PDMS, and curing to form the porous film which is uniformly distributed on the surface of the cavity porous film (1) at intervals; after the movable solenoid (3) is electrified, the intensity of the magnetic field is changed by adjusting the intensity of the voltage, so that the radial contraction of the magnetic endless belt with different amplitudes is realized. In this example, the width of the magnetic endless belt was 500 μm, and the pitch was designed to be 1.5mm. Also, in other embodiments, the dimensions may be modified and adjustedThis is entirely within the scope of the present disclosure, as simple alternatives readily occur to those skilled in the art.
In order to enable the movable solenoid (3) to shrink and exhibit wave-shaped axial peristaltic motion, the movable solenoid (3) should keep 0.5cm/min to 2cm/min of axial movement according to the intestinal bionic principle.
The air channels (6) and (7) at two sides are used for air inlet/exhaust through the micro air pump, and the whole porous film (1) of the cavity is deformed through the supporting film (8) for simulating the tension shrinkage of the intestinal tract. The length and the thickness of the side surfaces of the gas channels (6) and (7) at the two sides are consistent with those of the chip, and the width can be 5mm; the preparation is completed by twice casting of the aluminum alloy mould with PDMS and bonding encapsulation with plasma treatment.
The metabolic liquid collecting device (4) and the culture liquid perfusion device (5) are used for liquid perfusion and sealing of the whole cavity chip. The two devices are prepared by an aluminum die of a milling process, and the supporting film (8) and the cavity porous film (1) are sealed by using a plasma treatment bonding process. The cavity structure with the sealed periphery can realize slow perfusion of culture solution, form axial and circumferential shear stress inside and outside the three-dimensional cavity porous film, and form a similar micro-mechanical environment with the intestinal tract of a living body.
The metabolic liquid collecting device is arranged on the outer side of the film, and is distinguished from the culture liquid perfusion device in that the perfusion device is arranged on the upper half part of the outer side of the whole cavity chip, and the metabolic liquid collecting device is arranged on the lower half part of the whole cavity chip. The metabolic liquid collecting device (4) is separated from the culture liquid filling device (5) by a film.
Through the structure, multi-mechanical parameter stimulation is formed, and the multi-mechanical parameter stimulation is cultured and differentiated into the shape similar to human intestinal tracts and the types and the distribution of intestinal epithelial cells in the cavity porous film (8). And respectively marking specific proteins (such as actin and fibronectin) by combining with the existing intestinal organ chip (a Transwell model and a two-dimensional intestinal organ chip), performing morphological characterization of a confocal microscope, and comparing the formation states of intestinal villi.
Intestinal epithelial cells cultured inside the cavity can be analyzed for intestinal epithelial barrier function by recording transmembrane resistance techniques, indirectly reflecting the extent of intestinal cell gap junctions.
The intestinal epithelial cells can slowly flow the culture solution containing the fluorescein FD20 marked monosaccharide into the cavity porous membrane through the culture solution perfusion device (5), and perform fluorescein statistics through the metabolic solution collection device (4) so as to analyze digestion, absorption and permeation functions of the intestinal epithelial cells.
The probiotics can be introduced into the cavity porous film (1) for constructing the coexistence environment of intestinal tracts/bacteria, and comparing and analyzing the influence of coexistence of the probiotics and the bacteria on the morphology and the function of the chip. The rod pathogenic bacteria are introduced into the cavity porous film (1) and used for constructing a common enteritis disease model (such as Crohn); and (3) observing and analyzing the infection condition of pathogenic bacteria in the living intestinal environment with multiple mechanical parameters.
The preparation process of the three-dimensional cavity intestinal organ chip mainly comprises a three-dimensional cavity film, a micro-air channel and Fe 3 O 4 Three parts of the magnetic endless belt.
The method specifically comprises the following steps:
preparing a cavity film: first, a 30 μm thick layer of SU-8 negative photoresist was spin coated onto a silicon wafer at 2500 r/min. Vacuum dried at 95 ℃ for 20 minutes and then cooled to room temperature. The photomask is then contacted with the coated silicon wafer and exposed. Then, the wafer was subjected to heat treatment by heating at 95℃for 10 minutes, or post-exposure baking. The array of micropillars was then developed by immersing the silicon wafer in a developer for 10 minutes, followed by rinsing with water and drying in air. PDMS (mass ratio 20:1) was spin coated onto the micropillar array at 3000r/min and carefully peeled off after curing. The film was attached around the teflon hose one turn and the tight joint was achieved by semi-curing PDMS.
As shown in fig. 2, the method is divided into:
(A) Throwing a layer of 20 mu mSU-8 photoresist on the surface of the silicon wafer;
(B) Ultraviolet exposure treatment;
(C) A developing operation;
(D) Preparing an SU-8 micro-column template;
(E) Solidifying the formed template;
(F) Throwing a layer of PDMS by a spin coater;
(G) Peeling off the PDMS film;
(H) Cutting into rectangular films;
(I) Plasma treatment and bonding to form porous film.
(2) And (3) preparation of a micro-gas channel: the micro-air channel comprises two parts which are the same up and down, and each part is formed by pouring PDMS (mass ratio 10:1) into an aluminum mould and then solidifying. The aluminum mold was prepared by a milling process with two rectangular parallelepiped projections (height 150 μm, width 1000 μm). And the two parts are subjected to plasma treatment to realize fit packaging. (see FIG. 3).
The method specifically comprises the following steps:
(A) An aluminum die prepared by a milling process is used for preparing an upper symmetrical part and a lower symmetrical part of a chip;
(B) The cavity porous membrane is embedded in the upper symmetrical part and the lower symmetrical part;
(C) After plasma treatment, bonding and packaging;
(D) Embedding the support film on both sides of the peeled porous film;
(E) Plasma treatment;
(F) And (5) bonding and packaging.
(3)Fe 3 O 4 Magnetic endless belt: fe with diameter of 100nm 3 O 4 The particles were thoroughly mixed with PDMS (mass ratio 20:1) by means of a stirrer (power of the stirrer was 60W running for more than 4 h), then spin-coated onto an acrylic plate with a uniform surface at 4000r/min, and after waiting for curing, carefully peeled off. Activating the surface of the cavity PDMS film by Plasma, and stripping the stripped Fe 3 O 4 The magnetic films are uniformly adhered to the surfaces of the magnetic films at equal intervals. Finally, the three parts are assembled by a key and a process.
In the above preparation process, the applied equipment, the motion parameters of the equipment (such as power, time, etc.), the materials, the parameters of each material (such as proportion, particle size, etc.), the process parameters (such as temperature, etc.), etc. may be replaced in other embodiments, which are easily considered by those skilled in the art, and are utilized within the protection scope of the present disclosure.
The formed cavity intestinal organ chip integrates multiple mechanical parameters, can be used for realizing multi-mode motion simulation, and can be used for researching:
(1) Simulating intestinal tract segmental radial contraction and peristalsis: to simulate the radial contraction of the intestinal tract segments, a relationship between magnetic field strength and strain is first sought. Under the assumption that a cavity film with the same rigidity and thickness as those of living intestinal tissues can be prepared, the coomsol numerical simulation is utilized to establish the calibration relation between the magnetic field strength and the deformation (the stretching ratio of the diameter) of the PDMS film. Subsequently, the voltage of the solenoid is changed to find the deformation of the cavity film corresponding to the deformation. Finally, the sectional radial contraction of the cavity film is realized by a solenoid according to the frequency of 0.13 Hz-0.18 Hz. To simulate peristaltic waves of intestinal pushing chyme/drug forward, we will work on evenly distributed Fe 3 O 4 The magnetic endless belt alternately attracts and releases. The velocity of peristaltic waves is calculated by the time difference between the gaps of the magnetic ring belt and the two wave peaks. The relationship between the calibration of the different speeds of the solenoid (0.5 cm/s,1.0cm/s,1.5cm/s,2 cm/s) and the peristaltic wave speed of the cavity is set.
(2) The stressor simulation was implemented: the tension contraction simulation is realized by adopting a gas stretching technology similar to a two-dimensional intestinal organ chip (the gas pressure stretching film deformation is realized by utilizing two side channels). The difference is that we are facing the cavity stretching deformation, so that under the same deformation, the applied air pressure value obtained by Ansys simulation is different.
(3) Modeling the microfluidic flow rate versus shear stress relationship: firstly, calculating internal shaft shear stress in an ideal state through the flow rate of liquid in an intestinal tract of a living body; and secondly, introducing the value into a Comsol software, and reversely simulating the flow speed of the culture solution required by the cavity intestinal organ chip.
The parameters used in the above-described research process may be changed according to the specific circumstances. These are readily apparent to those skilled in the art and are utilized within the scope of the present disclosure.
The foregoing description of the preferred embodiments of the present disclosure is provided only and not intended to limit the disclosure so that various modifications and changes may be made to the present disclosure by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure.
While the specific embodiments of the present disclosure have been described above with reference to the drawings, it should be understood that the present disclosure is not limited to the embodiments, and that various modifications and changes can be made by one skilled in the art without inventive effort on the basis of the technical solutions of the present disclosure while remaining within the scope of the present disclosure.
Claims (11)
1. An integrated intestinal multi-mode movement three-dimensional cavity intestinal organ chip is characterized in that: comprising the following steps:
the device comprises a cavity porous membrane for culturing differentiated intestinal epithelial cells, wherein a supporting membrane is arranged on the outer side of the cavity porous membrane, the supporting membrane is connected with a gas channel, and the supporting membrane is driven to move through the air inlet/outlet of the gas channel, so that the cavity porous membrane is deformed to simulate tension shrinkage action;
the outer side of the cavity porous film is provided with a cavity provided with a containing area, and a culture solution perfusion area can be provided for the cavity porous film to form a micromechanical environment with axial and circumferential shear stress;
a plurality of closing magnetic tapes are embedded on the circumference of the cavity porous film, and the closing magnetic tapes can generate a magnetic field along with the energization of a solenoid which is movably arranged outside the cavity, so that the corresponding position of the cavity porous film is radially contracted;
the energizing voltage of the solenoid can be adjusted, and the radial contraction of the magnetic ring belt with different amplitudes can be realized by changing the magnetic field strength through adjusting the intensity of the voltage; in order to enable the intestinal tract bionic principle to shrink and present wave-shaped axial peristaltic motion, the moving solenoid keeps moving axially according to the intestinal tract bionic principle;
the specific process for simulating the intestinal tract sectional radial contraction and peristalsis comprises the following steps: to simulate the segmental radial contraction of the intestinal tract, firstly, the relation between the magnetic field strength and the strain is sought; under the condition of preparing a cavity film with the same rigidity and thickness as the living intestinal tissue, establishing a calibration relation between the magnetic field strength and the deformation of the cavity film; changing the voltage of the solenoid to find the deformation of the cavity film corresponding to the deformation; the sectional radial contraction of the cavity film is realized through a solenoid; to simulate peristaltic waves of intestinal canal pushing chyme or medicine advancing, the evenly distributed magnetic endless belt is alternately attracted and released; the speed of peristaltic waves is calculated by using the time difference between the gaps of the magnetic ring belt and the two wave peaks; setting the relation between different speed calibration of the solenoid and peristaltic wave speed of the cavity;
calculating internal shaft shear stress under ideal conditions through the liquid flow rate in the intestinal tract of a living body; based on the values, the flow rate of the culture solution required by the luminal intestinal organ chip was simulated reversely.
2. An integrated intestinal multi-modal movement three-dimensional cavity intestinal organ chip as claimed in claim 1, wherein: the cavity porous film is prepared from a flexible polydimethylsiloxane material, and the thickness of the cavity porous film is 3-5 mu m.
3. An integrated intestinal multi-modal movement three-dimensional cavity intestinal organ chip as claimed in claim 1, wherein: the closed magnetic tape is an annular magnetic tape and is formed by fully mixing magnetic particles with the cavity porous film and then solidifying the magnetic particles, and the magnetic particles are uniformly distributed on the surface of the cavity porous film at intervals.
4. An integrated intestinal multi-modal movement three-dimensional cavity intestinal organ chip as claimed in claim 1, wherein: the gas channels comprise two gas channels, are arranged on two sides of the cavity porous film, are made of the same material as the cavity porous film, are bonded and packaged by plasma treatment, and have the same length and thickness as the cavity porous film.
5. An integrated intestinal multi-modal movement three-dimensional cavity intestinal organ chip as claimed in claim 1, wherein: intestinal epithelial cells can be cultured on the inner side and the outer side of the cavity porous film, the intestinal organ chip is used for marking appointed proteins, the morphological characterization of a confocal microscope is carried out, and the formation state of intestinal villi is compared; the extent of intestinal cell gap junction is indirectly reflected by the analysis of the intestinal epithelial barrier function on the inside by recording the transmembrane resistance technique.
6. The method for preparing the three-dimensional cavity intestinal organ chip according to any one of claims 1 to 5, wherein the sum is: the method comprises the following steps:
preparing a cavity porous film: spin-coating a layer of SU-8 negative photoresist on a silicon wafer, cooling to room temperature after vacuum drying, contacting a photomask with the coated silicon wafer, exposing the wafer by heating, and performing heat treatment, or baking after exposure, the micro-column array is then developed by immersing the silicon wafer in a developing solution for a period of time, rinsing with water and drying in air, the flexible polydimethylsiloxane material is spin-coated on the micro-column array, stripping after curing, attaching a thin film around a Teflon hose for one circle, and realizing close joint by semi-curing the flexible polydimethylsiloxane material;
preparing a micro-gas channel: filling a flexible polydimethylsiloxane material into a mold, and then curing, wherein the mold comprises two parts with the same structure, each part is provided with at least two bulges, the two parts are oppositely arranged, and the fit packaging is realized through plasma treatment;
preparing a closed magnetic tape, and adding Fe 3 O 4 The particles are fully mixed with the flexible polydimethylsiloxane material, then the mixture is spin-coated on an acrylic plate with uniform surface, after curing, the mixture is peeled off, plasma is used for activating the surface of the cavity flexible polydimethylsiloxane material film, and the peeled Fe is removed 3 O 4 The magnetic films are uniformly adhered to the surfaces of the magnetic films at equal intervals;
and (5) finishing the assembly of the prepared three parts through keys and a process.
7. A method of operating a three-dimensional luminal intestinal organ chip according to any one of claims 1 to 5, characterised in that: the method comprises the following steps:
the supporting film is driven to move through the air inlet or the air outlet of the air channel, so that the cavity porous film is deformed to simulate and analyze tension shrinkage;
forming a micromechanical environment with axial and circumferential shear stress by changing the flow rate of the culture solution, and simulating and analyzing the relationship between the flow rate of the liquid and the shear stress;
by varying the voltage at which the solenoid is energized and the speed of movement of the solenoid, the occurrence of radial contraction and peristaltic waves of the intestinal tract is simulated and analyzed.
8. The method of operation of claim 7, wherein: when the radial contraction of the intestinal tract section is simulated and analyzed, under the condition that a cavity film with the same rigidity and thickness as those of living intestinal tissues is prepared, the calibration relation between the magnetic field strength and the deformation of the PDMS film is established by using simulation software, the voltage of a solenoid is changed to search the deformation of the cavity film corresponding to the deformation, and the sectional radial contraction of the cavity film is realized according to the set frequency through the solenoid.
9. The method of operation of claim 7, wherein: when peristaltic waves are simulated and analyzed, the closed magnetic tape is alternately attracted and released, the speed of the peristaltic waves is calculated by using the time difference between the gaps of the magnetic ring belt and the two wave peaks, and the relation between different speeds of the solenoid and the peristaltic wave speed of the cavity is determined.
10. The method of operation of claim 7, wherein: and when the tension shrinkage is simulated and analyzed, the two-side channels are utilized to realize the deformation of the pneumatic stretching film, and the relationship between different pneumatic pressures and the deformation is determined.
11. The method of operation of claim 7, wherein: when the relation between the liquid flow rate and the shear stress is simulated and analyzed, the internal shaft shear stress under ideal state is calculated according to the liquid flow rate in the intestinal tract of a living body, and the value is imported into simulation software to reversely simulate the flow rate of the culture solution required by the cavity intestinal organ chip.
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