CN115558601B - Mini mammal model and application thereof - Google Patents
Mini mammal model and application thereof Download PDFInfo
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- CN115558601B CN115558601B CN202211518830.4A CN202211518830A CN115558601B CN 115558601 B CN115558601 B CN 115558601B CN 202211518830 A CN202211518830 A CN 202211518830A CN 115558601 B CN115558601 B CN 115558601B
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Abstract
The invention discloses a mini-mammal model for drug effect, toxicity and drug generation detection and application thereof, wherein the mini-mammal model is formed by overlapping a lower substrate, a middle substrate, an upper substrate and a top plate; the lower substrate is an organ layer and is provided with a plurality of tissue culture chambers; the middle layer substrate is an artery and capillary vessel layer, the lower surface of the middle layer substrate is etched with a first micro-channel and a second micro-channel, and the second micro-channels are connected to the first micro-channel; the upper substrate is a vein layer, and a third micro-channel is etched on the upper substrate; the middle layer substrate is provided with a culture solution inlet communicated with the first micro-channel, and the top plate is provided with a culture solution outlet communicated with the third micro-channel. The mini-mammal model of the present invention can simulate intestinal absorption, liver metabolism, renal excretion and drug distribution, and on the mini-mammal, the time of administration curve, efficacy and toxicity of the drug can be measured.
Description
Technical Field
The invention relates to the technical field of drug screening, in particular to a mini mammal model for drug effect, toxicity and drug generation detection and application thereof.
Background
At present, the discovery cost of new drugs is high, and one of the important reasons is animal experiments. Because of individual differences among experimental animals, scientists need to use a plurality of similar animals to perform the same experiment and then average the same, so that the dosage of the experimental animals is greatly increased, and the research and development cost of new medicines is greatly improved.
The organ chip is an organ physiological micro system constructed on a chip with the size of a glass slide, and comprises key elements of organ microenvironment such as living cells, tissue interfaces, biological fluid, mechanical force and the like. The human body simulation system can simulate main structural functional characteristics of different tissues and organs of a human body and complex organ connection in vitro, is used for predicting the response of the human body to medicines or external different stimuli, and has wide application prospects in the fields of life science and medical research, new medicine research and development, personalized medicine, toxicity prediction, biological defense and the like.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a mini-mammal model based on an organ-chip technology, which can simulate intestinal absorption, liver metabolism, kidney excretion and drug distribution, and on which the time-of-drug curve, drug effect and toxicity of a drug can be measured.
In order to solve the technical problems, the invention provides the following technical scheme:
the first aspect of the invention provides a mini mammal model, which is formed by overlapping a lower substrate, a middle substrate, an upper substrate and a top plate from bottom to top in sequence; wherein,,
the lower substrate is an organ layer and is provided with a plurality of tissue culture chambers which are respectively used for culturing different micro tissues so as to simulate mammalian organs;
the middle layer substrate is an artery and capillary vessel layer, a first micro-channel representing an arterial vessel and a plurality of second micro-channels representing capillary vessels are etched on the lower surface of the middle layer substrate, the first micro-channel and the second micro-channels are respectively positioned above the tissue culture chambers and are communicated with the corresponding tissue culture chambers, and porous membranes are arranged between the tissue culture chambers and the first micro-channels and the second micro-channels; the plurality of second micro-channels are each connected to the first micro-channel;
the upper substrate is a vein layer, a third micro-channel representing a vein is etched on the upper substrate, and the third micro-channel is respectively arranged above the first micro-channel and the second micro-channel; the tail ends of the first micro-channel and the third micro-channel are provided with corresponding interfaces, and the third micro-channel is communicated with the first micro-channel and the second micro-channel below through the interfaces;
the medium layer substrate is provided with a culture solution inlet communicated with the first micro-channel, the top plate is provided with a culture solution outlet communicated with the third micro-channel, and the culture solution inlet and the culture solution outlet are communicated with an external culture medium circulating device so as to realize the internal circulation of culture solution in the first micro-channel, the second micro-channel, the third micro-channel and the tissue culture chamber.
In the present invention, the first microchannel corresponds to an arterial blood vessel, the second microchannel corresponds to a capillary blood vessel, and the third microchannel corresponds to a venous blood vessel, and since the first microchannel and the second microchannel pass over the tissue culture chamber, the culture solution in the microchannels and the culture solution in the tissue culture chamber are communicated, thereby connecting each culture chamber and the micro-tissue cultured therein.
In the present invention, the organ layer may also be formed by laminating a plurality of plates together. The micro-tissue cultured in the tissue culture chamber can be mammalian primary tissue, cell balls, organoids and the like, and the culture mode can be two-dimensional culture or three-dimensional culture.
Further, the bottom surface of the tissue culture chamber is a low-adhesion superhydrophobic surface with a micro-nano morphology, and the contact angle of the surface with an aqueous phase solution is larger than 120 degrees;
or the bottom surface of the tissue culture chamber is modified with a micro-nano morphology low-adhesion hydrophilic polymer coating, and the contact angle between the polymer coating and the aqueous phase solution is smaller than 90 degrees.
In the present invention, the bottom surface of the tissue culture chamber is a low adhesion surface modified so that when the micro-tissue is cultured, the micro-tissue does not adhere to the bottom wall of the chamber and disintegrate.
In one embodiment of the invention, the method for forming the low adhesion superhydrophobic surface is as follows: mixing nano silicon dioxide particles, normal hexane and chloroform, and then carrying out ultrasonic treatment to disperse the nano silicon dioxide particles in the mixed solution; and then, immersing the polymethyl methacrylate (PMMA) plate into the mixed solution, taking out and airing to obtain the low-adhesion superhydrophobic surface.
Preferably, the method for forming the low-adhesion superhydrophobic surface comprises the following steps: weighing hydrophobic nanometer silicon dioxide particles with diameters of 2-200 nm and 0.25-2 g, and weighing 20-500 mL normal hexane and 0.5-50 mL chloroform. The materials are mixed and then subjected to ultrasonic treatment, so that the nano silicon dioxide particles are completely dispersed in the mixed solution. Immersing the PMMA plate into the solution for about 5-300 percent s, taking out and airing to obtain the PMMA plate with the super-hydrophobic surface.
In another embodiment of the present invention, the method of forming the low adhesion superhydrophobic surface is: immersing a Polydimethylsiloxane (PDMS) plate into tetraethyl orthosilicate to swell, then taking out the swelled PDMS plate, and placing the swelled PDMS plate into an ethylenediamine water solution; and then taking out the PDMS plate, and carrying out heat treatment after washing to obtain the super-hydrophobic surface.
Preferably, the method for forming the low-adhesion superhydrophobic surface comprises the following steps: immersing the PDMS plate into tetraethyl orthosilicate at 30-70 ℃ for 10-200 min, then taking out the swelled PDMS plate from the tetraethyl orthosilicate solution, and immediately floating in 5% -40% ethylenediamine water solution. 3-24 and h, taking out and washing with deionized water for 3-5 times, and performing heat treatment in an oven for 0.5-5h to obtain the PDMS plate with the super-hydrophobic surface.
In yet another embodiment of the present invention, a method of forming the low adhesion superhydrophobic surface includes the steps of:
a. pouring the prepolymer of the elastic resin on a super-hydrophobic template with a micro-nano structure, polymerizing the prepolymer of the elastic resin into a first elastic solid, and stripping the first elastic solid from the template;
b. performing silanization modification on the surface of the first elastic solid, taking the silanized first elastic solid as a template, and pouring a prepolymerization liquid of elastic resin to polymerize the prepolymerization liquid of the elastic resin into a second elastic solid;
c. and stripping the second elastic solid from the silanized first elastic solid template, wherein the surface of the second elastic solid forms the low-adhesion superhydrophobic surface.
The super-hydrophobic template with the micro-nano structure can be natural materials, such as cicada wings, lotus leaves and the like; the material can also be prepared by using a manual method, such as a method of surface etching an aluminum plate, surface etching a high polymer plate, MEMS processing, surface enrichment of silica micro-nano particles, surface spraying of super-hydrophobic coating and the like.
Further, the preparation method of the low-adhesion hydrophilic polymer coating comprises the following steps:
s1, mixing glycidyl methacrylate and other polymerization monomers in water, and adding tetramethyl ethylenediamine and an initiator to perform copolymerization; after the reaction is finished, dialyzing the copolymer solution, and removing unreacted monomers and an initiator to obtain a high polymer coating liquid;
s2, pretreating the bottom surface of the tissue culture chamber to enable the bottom surface to generate polar groups, and then placing the pretreated bottom surface into the polymer coating liquid for soaking treatment; then taking out, cleaning the polymer coating liquid on the surface, and drying to form a low-adhesion hydrophilic polymer coating on the bottom surface of the tissue culture chamber;
wherein the other polymerization monomers comprise one or more of ethyl 2- (2-methoxyethoxy) methacrylate, methoxyethyl methacrylate, methyl dimethacrylate, hexafluorobutyl acrylate and methyl methacrylate; the polar group comprises one or more of hydroxyl, amino and carboxyl.
Further, in step S1, the mixing time of glycidyl methacrylate and other polymerization monomers in water is 5-30 min to ensure uniform mixing.
Further, in the step S1, the addition concentration of the tetramethyl ethylenediamine is 0.1wt% to 3wt%, and the addition concentration of the initiator is 0.1wt% to 3wt%.
Further, in step S1, the initiator may be an initiator commonly used in the art, preferably potassium persulfate. The time for the copolymerization is preferably 30 min-1 d.
Further, in step S1, the dialysis specifically includes: and (3) completely dialyzing the copolymer solution for two days by using a dialysis membrane, and changing the solution every 6-12 h to remove monomers and small molecules which do not undergo polymerization reaction, wherein the solution in the dialysis bag is the polymer coating solution.
In the step S2, hydroxyl, amino, carboxyl and other groups are introduced into the bottom surface of the tissue culture chamber, so that the hydrophilic modification liquid can be firmly bonded on the bottom surface of the tissue culture chamber through covalent bonds, and a polymer coating with a micro-nano morphology on the surface is formed. Preferably, the tissue culture chamber is treated with plasma so that polar groups are introduced into its bottom surface. For example, oxygen plasma treatment is employed to introduce hydroxyl groups.
Further, in the step S2, the temperature of the soaking treatment is 30-70 ℃, and the time of the soaking treatment is 30 min-5 d; the drying temperature is 0-75deg.C, and the drying time is 30 min-5 d.
Further, a through hole is formed in the bottom surface of the tissue culture chamber, and the through hole is used for extending the micro stirring paddle or the sensor into the tissue culture chamber. Since the tissue culture chamber is superhydrophobic, the culture fluid does not leak out of the through-hole at the bottom.
Further, the mini-mammal model has a similar appearance to a real mammal, thereby facilitating discrimination of the species of the simulated mammal.
Further, the location of at least one tissue culture chamber in the mini-mammalian model corresponds to the location of the organ it represents in the mammalian body and is similar in shape to the organ it represents, thus facilitating accurate placement of the corresponding micro-tissue in the tissue culture chamber.
Further, the tissue culture chamber includes a brain culture chamber, an eye culture chamber, a nose culture chamber, an ear culture chamber, a tongue culture chamber, a trachea culture chamber, a heart culture chamber, a lung culture chamber, a liver-intestine culture chamber, a kidney culture chamber, a stomach culture chamber, a pancreas culture chamber, a spleen culture chamber, a skin culture chamber, a fat culture chamber, a bone marrow culture chamber, a muscle culture chamber, a testis culture chamber, and a tumor culture chamber, but is not limited to the above-mentioned organ culture chamber.
Further, the culture fluid inlet communicates with a first microchannel above the lung culture chamber and the culture fluid outlet communicates with a tip of a third microchannel above the heart culture chamber.
Further, the porous membrane between the tissue culture chamber and the first micro-channel and the second micro-channel is used for culturing vascular endothelial cells, and immune cells are placed above the vascular endothelial cells.
Further, an airway is connected to the side walls of some tissue culture chambers, which is in communication with the outside to provide oxygen to the tissue culture chambers. The airways are preferably also superhydrophobic so that the culture fluid does not flow out through the airways.
Further, the liver-intestine culture chamber comprises a liver tissue culture region and an intestinal cell culture region positioned below the liver tissue culture region, wherein the liver tissue culture region is used for culturing liver micro-tissues, the liver micro-tissues are separated from a first micro-channel and a second micro-channel which are positioned above the liver tissue culture region by a porous membrane, and the upper surface of the porous membrane is used for culturing vascular endothelial cells, and immune cells are further cultured on the vascular endothelial cells.
The liver tissue culture area and the intestinal cell culture area are separated by another porous membrane, and the intestinal cells are cultured on the lower surface of the porous membrane; the intestinal cell culture area communicates with the outside through a separate digestive channel, and the digestive channel is used for simulating the circulating flow of digestive juice.
Further, the number of the kidney culture chambers is two, wherein one kidney culture chamber is used for culturing kidney micro-tissues and simulating kidney metabolic functions; the other kidney culture chamber is provided with a dialysis membrane and is communicated with the outside through a separate elimination channel for simulating the elimination of wastes and medicines in the body.
Further, the mammal includes, but is not limited to, a commonly used laboratory animal such as a mouse, rat, monkey, etc.
In a preferred embodiment, the present invention provides a mini-rat model comprising 19 organs, a blood circulation system, a excretory system, and a functional immune system, which can survive more than two worlds.
The invention also discloses application of the mini mammal model in drug effect detection, toxicity detection or drug generation detection.
Compared with the prior art, the invention has the beneficial effects that:
1. the mini-mammalian model of the present invention, which contains micro-tissues (primary tissues, organoids or cytoballs), does not model organs in cells or discrete combinations of cells; the tissue culture zone has a low adhesion surface, so that the tissue or organoid functionality is present in suspension in the mini animal model for a prolonged period of time; the tissue culture area is connected with a micro-channel system which can provide nutrition and oxygen for the micro-tissues; the mini mammal has the shape profile and organ distribution similar to those of the corresponding mammal, has the shape similar to that of the corresponding organ, is easy to distinguish, and has good imitation. The mini-mammal can simulate ADME process of the drug, namely intestinal absorption, liver metabolism, distribution and renal elimination process, and can measure time of drug curve, drug effect and toxicity of the drug.
2. The mini rat model provided by the invention can survive more than two worlds, can easily study pharmacodynamics, systemic toxicity and drug generation of the drug, and opens up an effective way for reducing individual differences of experimental animals.
3. Particularly, considering that the animals such as monkeys and the like can be divided into hundreds of monkey chips, the invention can reduce the animal consumption of the industry by at least one order of magnitude, thereby practically promoting the 3R principle to be practiced in the field of new medicine development.
Drawings
FIG. 1 is an electron micrograph of a surface of polydimethylsiloxane after twice overmolding with lotus leaves;
FIG. 2 shows the state of droplets on the surface of the super-hydrophobic PDMS;
FIG. 3 is a bright field photograph of tumor spheres on a PDMS superhydrophobic surface;
FIG. 4 shows the change in contact angle after 12 repeated uses;
FIG. 5 is a surface electron micrograph of a polydimethyl siloxane sheet of silica microbubbles;
FIG. 6 is a bright field photograph of surface tumor spheres of a polydimethyl siloxane sheet of silica microbubbles;
FIG. 7 is a photograph of a super hydrophobic PMMA surface electron microscope;
FIG. 8 is a bright field photograph of a superhydrophobic PMMA surface, tumor spheres;
FIG. 9 is an atomic force microscope image of a polymer coating surface;
FIG. 10 shows the adsorption of fluorescent proteins on modified PDMS surface (A) and unmodified PDMS surface (B);
FIG. 11 is a tumor sphere formed on the surface of a polydimethylsiloxane polymer coating;
FIG. 12 is a graph showing the disintegration of kidney micro-tissue on a normal surface;
FIG. 13 is a photograph of a mini mouse model;
FIG. 14 is a plan view of vein, artery and capillary layers and organ layers of a mini mouse model;
FIG. 15 is a view of the type of tissue contained within each chamber;
FIG. 16 is a bright field image of each tissue;
FIG. 17 is an organ structure diagram of a mini mouse model;
FIG. 18 is a major organ mass ratio of a real rat;
FIG. 19 is the direction of blood flow in a mini-mouse model;
FIG. 20 is a design of a mini-mouse model kidney elimination unit;
FIG. 21 is a graph of sodium fluorescein elimination at various blood and urine flow rates;
FIG. 22 is a design of a mini mouse model liver and bowel unit;
FIG. 23 is an erlotinib drug time curve based on the mini-mouse model;
FIG. 24 is a graph showing the results of evaluation of systemic toxicity and efficacy of doxorubicin based on the mini-mouse model;
FIG. 25 is a design drawing of a mini manikin;
FIG. 26 is a design drawing of a mini dog model;
FIG. 27 is a design drawing of a mini monkey model;
FIG. 28 is a design drawing of a mini pig model;
wherein: 1. a tissue culture chamber; 2. an airway; 3. a micro-stirrer; 4. a micro-tissue; 5. vascular endothelial cells; 6. an immune cell; 7. eliminating channels; 8. a porous membrane; 9. liver micro-tissue; 10. an intestinal cell; 11. a digestive tract; 12. a lung; 13. left atrium and ventricle; 13', right atrium and ventricle; 14-23, 14'-23', capillary end interfaces;
a. a heart culture chamber; b. a liver-gut culture chamber; c. a spleen culture chamber; d. a lung culture chamber; e. a kidney culture chamber; f. a brain culture chamber; g. an eye culture chamber; h. an ear culture chamber; i. a bone marrow culture chamber; j. a muscle culture chamber k, a trachea culture chamber; l, a fat culture chamber; m, testis culture chamber; n, pancreas culture chambers; o, gastric culture chamber; p, tumor culture chamber; q, nasal culture chamber; r, tongue culture chamber; s, skin culture chamber.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Example 1: using natural material as template to make super-hydrophobic surface
Fixing lotus leaves on a glass plate, pouring liquid polydimethylsiloxane on the surface of the lotus leaves, polymerizing the liquid polydimethylsiloxane into solid, stripping the solidified polydimethylsiloxane from the lotus leaves to serve as a template for the next step, silanizing and modifying the surface of the polydimethylsiloxane template, pouring the liquid polydimethylsiloxane on the template, heating for polymerization, stripping the newly solidified polydimethylsiloxane from the silanized and modified polydimethylsiloxane template, and finishing the preparation of the superhydrophobic polydimethylsiloxane plate, wherein an electron microscope picture of the surface of the newly solidified polydimethylsiloxane is shown in figure 1, and the electron microscope picture has a superhydrophobic micro-nano structure with a contact angle of more than 120 DEG (figure 2).
Low adhesion characterization:
the plane is used for a tumor cell balling experiment, human embryo lung fibroblast (MRC-5) and human lung adenocarcinoma cell (NCI-H1792) are mixed and cultured, the culture medium is RPMI 1640+10% FBS, the mixture is placed in a hole with the super-hydrophobic surface, the culture ratio of the fibroblast to the cancer cell is 1:1, the culture environment is 37 ℃, and the culture environment is 5% CO 2 . After 3 days the tumor cells did not adhere, but were balled (fig. 3), demonstrating the low adhesion of the superhydrophobic surface.
Durability characterization:
the test reproducibility showed that the wells were filled with various cell culture media for 48 hours, then poured off, washed, air dried, and the above experiment was repeated 12 times, the contact angle was measured again, still greater than 120 ° (fig. 4), indicating that the low adhesion surface could be reused at least 12 times for a continuous use period of more than 24 days.
Example 2: direct preparation of polydimethylsiloxane superhydrophobic surfaces
A polydimethylsiloxane plate was immersed in tetraethyl orthosilicate at 50℃for 20 min. Then, the tetraethyl orthosilicate-swollen polydimethylsiloxane plate was taken out of the tetraethyl orthosilicate solution, immediately floated in a 10% aqueous solution of ethylenediamine, and silica microbubbles were gradually formed on the surface of the polydimethylsiloxane plate. 10 After h, the polydimethylsiloxane plate with silica microbubbles was removed and rinsed 3 times with deionized water. Finally, the polydimethylsiloxane plate with silica microbubbles was heat treated in an oven 1 h. The electron microscope photograph of the prepared superhydrophobic surface is shown in fig. 5.
Low adhesion characterization:
the plane is used for a tumor cell balling experiment, human embryo lung fibroblast (MRC-5) and human lung adenocarcinoma cell (NCI-H1792) are mixed and cultured, the culture medium is RPMI 1640+10% FBS, the mixture is placed in a hole with the super-hydrophobic surface, the culture ratio of the fibroblast to the cancer cell is 1:1, the culture environment is 37 ℃, and the culture environment is 5% CO 2 . After 3 days the tumor cells did not adhere, but were balled (fig. 6), demonstrating the low adhesion of the superhydrophobic surface.
Durability characterization:
the test reproducibility showed that the wells were filled with cell culture medium (1640 medium +10% fetal bovine serum) for 48h, then poured off, washed, air dried, and the above experiment was repeated 12 times, finally measuring a contact angle of 135.8 °, still greater than 120 °, indicating that the low adhesion surface could be reused at least 12 times for a continuous use period of more than 24 days.
Example 3: preparation of polymethyl methacrylate superhydrophobic surface
Hydrophobic nano silicon dioxide particles with the diameter of 20 nm and 0.25 and g are weighed, 50 mL normal hexane and 2.5 mL chloroform are weighed, mixed and then subjected to ultrasonic treatment, so that the nano silicon dioxide particles are completely dispersed in a mixed solution, a polymethyl methacrylate plate is immersed in the solution for about 15 s, taken out and dried, and the polymethyl methacrylate super-hydrophobic surface (figure 7) is obtained.
Low adhesion characterization:
the plane is used for the tumor cell balling experiment, and the human embryo lung fibroblast (MRC-5) and human lung adenocarcinoma cell (NCI-H1792) are mixed and cultured,the culture medium is RPMI 1640+10% FBS, and is placed in the hole with the super-hydrophobic surface, the culture ratio of fibroblast to cancer cell is 1:1, the culture environment is 37 ℃, and the CO content is 5% 2 . After 3 days the tumor cells did not adhere, but were balled (fig. 8), demonstrating the low adhesion of the superhydrophobic surface.
Durability characterization:
the test reproducibility showed that the well plate was added to cell culture medium (1640 medium +10% fetal bovine serum) for 48h, then poured off, washed, air dried, and the above experiment was repeated 12 times, finally measuring a contact angle of 132.6 °, still greater than 120 °, indicating that the low adhesion surface could be reused at least 12 times for a continuous use time of more than 24 days.
Example 4: preparation of polydimethylsiloxane superhydrophilic surface
Uniformly mixing 2 mL methyl methacrylate, 0.04mL poly glycidyl methacrylate and 38 mL water for 10 min, adding 0.4 g potassium persulfate and 2 mL water, fully dissolving, adding 0.04mL TEMED, carrying out copolymerization reaction at 25 ℃ for 15 min, stopping the reaction after the color of the solution is changed from transparent to milky white, immediately transferring into a 1.5W dialysis bag for dialysis for two days, and changing the liquid every 12 h to remove monomers and small molecules which do not have polymerization reaction, wherein the solution in the dialysis bag is the polymer coating liquid.
Firstly, hydroxyl is generated on the surface of polydimethylsiloxane through oxygen plasma, then the polymer coating liquid is soaked in the surface 1 h, then the polymer coating liquid is removed, and the polymer coating liquid is washed three times with deionized water and dried at 75 ℃ for 1 h.
First, the surface is characterized by atomic force microscopy, and as is apparent from fig. 9, after modification, the surface has a layer of high molecular polymer, and the high molecular polymer forms a nano-gully structure on the surface.
Protein adsorption prevention characterization was then performed. The fluorescent-labeled secondary antibody solution was injected onto the modified and unmodified surfaces, respectively, and it was evident that the fluorescence intensity was high on the unmodified surface, indicating that protein adsorption was severe, whereas on the modified surface, almost no fluorescence was detected, indicating that the coating well protected against protein adsorption (fig. 10).
Finally, cell adhesion prevention characterization was performed. Human embryonic lung fibroblasts (MRC-5) and human lung adenocarcinoma cells (NCI-H1792) were mixed and cultured in RPMI 1640+10% FBS. The culture ratio of fibroblast to cancer cell is 1:1, the culture environment is 37 ℃, and the CO content is 5% 2 . After 3 days, the cells did not adhere, but formed tumor spheres (fig. 11), confirming the ability of the coating to prevent cell adhesion. The same surface was successfully treated by 5 consecutive tumor balling experiments, demonstrating the durability of the low adhesion surface.
Renal tissue was placed on a non-low adhesion surface and cells were found to climb out, and the tissue disintegrated very rapidly (fig. 12).
Example 5: mini mouse model
This embodiment provides a mini mouse model, as shown in fig. 13, which resembles a real mouse. As shown in fig. 14, the mini mouse model is formed by overlapping an organ layer (PMMA), an artery and capillary layer (PDMS) and a vein layer (PMMA) from bottom to top, and the lower layer (i.e., the organ layer) of the mini mouse model contains 19 PMMA superhydrophobic chambers: heart culture chamber a, liver-intestine culture chamber b, spleen culture chamber c, lung culture chamber d, kidney culture chamber e, brain culture chamber f, eye culture chamber g, ear culture chamber h, bone marrow culture chamber i, muscle culture chamber j, trachea culture chamber k, fat culture chamber l, testis culture chamber m, pancreas culture chamber n, stomach culture chamber o, tumor culture chamber p, nose culture chamber q, tongue culture chamber r, skin culture chamber s (fig. 15), the bottom surface of the superhydrophobic chamber is a superhydrophobic surface, and the contact angle with aqueous solution is greater than 120 °. The super-hydrophobic modification process comprises the following steps: weighing hydrophobic nano silicon dioxide particles with the diameter of 20 nm and 0.25 and g, weighing 50 mL normal hexane and 2.5 mL chloroform, mixing, performing ultrasonic treatment to completely disperse the nano silicon dioxide particles in the mixed solution, immersing a PMMA plate in the solution for about 15 s, taking out and airing to obtain the PMMA super-hydrophobic surface.
Each chamber contained a primary microstructure including brain, eye, nose, ear, tongue, trachea, heart, lung, liver, kidney, stomach, pancreas, spleen, skin, fat, bone marrow, muscle, testis, and tumor (fig. 16). The acquisition method of each micro-tissue is as follows: firstly, shearing the organ by using scissors, then masking, and finally sieving, and reserving 70-100 mu m tissue particles, namely, micro-tissues simulating the organ in a chip, wherein the culture medium used by each micro-tissue is shown in the table 1 below.
TABLE 1 culture Medium for various micro-tissues
In the present invention, the outline of each chamber is similar to the corresponding organ, and the distribution of the chambers is similar to the distribution of the real organs in the body (fig. 15), so that accurate positioning and identification of various micro tissues are facilitated.
As shown in FIG. 17, a porous membrane 8 is clamped in the middle of each tissue culture chamber 1, vascular endothelial cells 5 are cultured on the membrane, immune cells 6 are arranged above the vascular endothelial cells 5, and micro-tissues 4 are arranged below the vascular endothelial cells 5. The bottom of the tissue culture chamber 1 is provided with a through hole, and the through hole extends into a micro stirrer 3 to stir the culture solution in the chamber for enhancing mass transfer. Since the tissue culture chamber 1 is superhydrophobic, the culture fluid does not leak out of the small hole at the bottom.
An air passage 2 is also arranged in the tissue culture chamber 1 and communicated with the peripheral air to supplement oxygen for the micro-tissue 4 in the chamber. Airway 2 is also superhydrophobic and the modification method, as described above, does not allow the cell culture fluid to leak out. The micro-tissue 4, vascular endothelial cells 5 and immune cells 6 constitute organs of the mini mouse model. The mass ratio between major organs of the mini-mouse model was consistent with the mass ratio of the corresponding organs in the real mouse (fig. 18).
As shown in fig. 14, arteries and capillaries of the mini mouse model were etched on the middle PDMS slab, the capillaries were located right above the chamber shown in fig. 17, and capillary networks of different organs were connected by arterial vessels. Veins of the mini mouse model were engraved on an upper PMMA plate (fig. 14) which was also attached to an external peristaltic pump and culture media tank (fig. 19), the PDMS plate of the arterial and capillary layers being held against under the upper PMMA plate.
As shown in fig. 19, "arterial blood" first enters the lungs 12 from the media tank, then the left atrium and ventricle 13, and then shunts through the porous membrane to the various organs under the arterial and capillary layers, which becomes "venous blood". Blood then enters the venous layer (14 to 14',15 to 15',16 to 16',17 to 17',18 to 18',19 to 19',20 to 20',21 to 21',22 to 22',23 to 23') vertically via the capillary end interfaces 14 to 23, and the blood of the capillary end interfaces 14'-23' merges into the right atrium and ventricle 13', and then "venous blood" enters the culture medium tank from the right atrium and ventricle 13', becoming "arterial blood" again. Then, fresh "blood" flows again into the lungs 12, completing a "blood circulation" process. When "blood" circulates, the micro-tissue in the mini-mouse model can survive for a long period of time, similar to a simulated mouse, and has life.
Referring to fig. 15, the mini mouse model has two kidneys. Wherein, kidney on one side of abdomen is provided with kidney micro-tissue for detecting kidney toxicity of the medicine; while the kidneys close to the back are used for the excretion of waste and medicines in the body, under which a separate elimination channel 7 is specially provided (fig. 20). An exemplary sodium fluorescein (molecular weight 320) elimination curve is shown in figure 21.
Referring to fig. 22, in the mini mouse model, the intestine is designed under the liver micro-tissue 9, the middle is separated by the porous membrane 8, and the intestinal cells 10 are cultured on the lower surface of the porous membrane 8, and a dense intestinal membrane is formed. The intestinal cell culture area is also in communication with the outside through a separate digestion channel 11 to effect circulation of the digestive fluid stream. The drug is fed from the digestive tract 11 and may be administered orally in a simulated manner, the drug being first absorbed by the intestine and then metabolized by the liver and finally entering simulated blood.
In this example, one adult rat was sacrificed, various tissues thereof were extracted, and 3 parallel mini mouse models were prepared, each of which was 10 and cm long, and the erlotinib dose curve (dose 1.08 mg) was measured using the mini mouse model. As can be seen from fig. 23, the blood concentration tended to rise and then fall, similar to the curve in the case of the actual drug, and the error of each data point was small.
In addition, the systemic toxicity and efficacy of doxorubicin were also measured using the mini mouse model, and it can be seen that doxorubicin was differentially toxic and efficacy to various organs (fig. 24).
Example 6: mini mannequin, mini dog model, mini monkey model and mini pig model
FIGS. 25-28 are schematic illustrations of these mini-mammal models, including arterial and capillary layers, venous layers and organ layers, in which micro-tissues of corresponding species are placed in the chamber to perform drug evaluations in place of corresponding real mammals.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.
Claims (7)
1. A mini mammal model is characterized in that the mini mammal model is formed by overlapping a lower substrate, a middle substrate, an upper substrate and a top plate from bottom to top in sequence; wherein,,
the lower substrate is an organ layer, and a plurality of tissue culture chambers are formed on the lower substrate and are respectively used for culturing different micro tissues so as to simulate each organ of a mammal;
the middle layer substrate is an artery and capillary vessel layer, a first micro-channel representing an arterial vessel and a plurality of second micro-channels representing capillary vessels are etched on the lower surface of the middle layer substrate, the first micro-channel and the second micro-channels are positioned above the tissue culture chambers and are communicated with the corresponding tissue culture chambers, and porous membranes are arranged between the tissue culture chambers and the first micro-channels and between the tissue culture chambers and the second micro-channels; the plurality of second micro-channels are each connected to the first micro-channel;
the upper substrate is a vein layer, a third micro-channel representing a vein is etched on the upper substrate, and the third micro-channel is respectively arranged above the first micro-channel and the second micro-channel; the tail ends of the first micro-channel and the third micro-channel are provided with corresponding interfaces, and the third micro-channel is communicated with the first micro-channel and the second micro-channel below through the interfaces;
the medium layer substrate is provided with a culture solution inlet communicated with the first micro-channel, the top plate is provided with a culture solution outlet communicated with the third micro-channel, and the culture solution inlet and the culture solution outlet are communicated with an external culture medium circulating device so as to realize the circulation of culture solution in the first micro-channel, the second micro-channel, the third micro-channel and the tissue culture chamber;
the mini-mammal model has a similar profile to a real mammal; the location of the tissue culture chamber in the mini-mammalian model corresponds to the location of the organ it represents in the mammalian body and is similar to the appearance of the organ it represents;
the tissue culture chamber consists of a brain culture chamber, an eye culture chamber, a nose culture chamber, an ear culture chamber, a tongue culture chamber, a trachea culture chamber, a heart culture chamber, a lung culture chamber, a liver-intestine culture chamber, a kidney culture chamber, a stomach culture chamber, a pancreas culture chamber, a spleen culture chamber, a skin culture chamber, a fat culture chamber, a bone marrow culture chamber, a muscle culture chamber, a testis culture chamber and a tumor culture chamber;
the culture solution inlet is communicated with a first micro-channel above the lung culture chamber, and the culture solution outlet is communicated with the tail end of a third micro-channel above the heart culture chamber; the porous membrane between the tissue culture chamber and the first micro-channel and the second micro-channel is used for culturing vascular endothelial cells, and immune cells are placed above the vascular endothelial cells;
the liver-intestine culture chamber comprises a liver tissue culture area and an intestine cell culture area positioned below the liver tissue culture area, wherein the liver tissue culture area is used for culturing liver micro-tissues, the liver micro-tissues are separated from a first micro-channel and a second micro-channel which are positioned above the liver tissue culture area through a porous membrane, the upper surface of the porous membrane is used for culturing vascular endothelial cells, and immune cells are further cultured on the vascular endothelial cells;
the liver tissue culture area and the intestinal cell culture area are separated by another porous membrane, and the intestinal cells are cultured on the lower surface of the porous membrane; the intestinal cell culture area is communicated with the outside through an independent digestion channel, and the digestion channel is used for simulating the circulating flow of digestive juice;
the bottom surface of the tissue culture chamber is a low-adhesion superhydrophobic surface with a micro-nano morphology, and the contact angle between the surface and an aqueous phase solution is larger than 120 degrees; the method for forming the low-adhesion superhydrophobic surface comprises the following steps: mixing nano silicon dioxide particles, normal hexane and chloroform, and then carrying out ultrasonic treatment to disperse the nano silicon dioxide particles in the mixed solution; then, immersing the PMMA plate into the mixed solution, taking out and airing to obtain the low-adhesion superhydrophobic surface;
or the bottom surface of the tissue culture chamber is modified with a micro-nano morphology low-adhesion hydrophilic polymer coating, and the contact angle between the polymer coating and the aqueous phase solution is smaller than 90 degrees; the preparation method of the low-adhesion hydrophilic polymer coating comprises the following steps:
s1, mixing glycidyl methacrylate and other polymerization monomers in water, and adding tetramethyl ethylenediamine and an initiator to perform copolymerization; after the reaction is finished, dialyzing the copolymer solution, and removing unreacted monomers and an initiator to obtain a high polymer coating liquid;
s2, pretreating the bottom surface of the tissue culture chamber to enable the bottom surface to generate polar groups, and then placing the pretreated bottom surface into the polymer coating liquid for soaking treatment; then taking out, cleaning the polymer coating liquid on the surface, and drying to form a low-adhesion hydrophilic polymer coating on the bottom surface of the tissue culture chamber;
wherein the other polymerization monomer is methyl methacrylate; the initiator is potassium persulfate; the polar group comprises one or more of hydroxyl, amino and carboxyl.
2. The mini-mammalian model of claim 1, wherein the method of forming the low adhesion superhydrophobic surface comprises: immersing a PDMS plate into tetraethyl orthosilicate to swell, then taking out the swelled PDMS plate, and placing the swelled PDMS plate into an ethylenediamine water solution; and then taking out the PDMS plate, and carrying out heat treatment after washing to obtain the low-adhesion superhydrophobic surface.
3. The mini-mammalian model of claim 1, wherein the method of forming the low adhesion superhydrophobic surface comprises the steps of:
a. pouring the prepolymer of the elastic resin on a super-hydrophobic template with a micro-nano structure on the surface, polymerizing the prepolymer of the elastic resin into a first elastic solid, and stripping the first elastic solid from the template;
b. performing silanization modification on the surface of the first elastic solid, taking the silanized first elastic solid as a template, and pouring a prepolymerization liquid of elastic resin to polymerize the prepolymerization liquid of the elastic resin into a second elastic solid;
c. and stripping the second elastic solid from the silanized modified first elastic solid template, so that the low-adhesion super-hydrophobic surface is formed on the surface of the second elastic solid.
4. The mini-mammalian model of claim 1, wherein the bottom surface of the tissue culture chamber is perforated with through holes for inserting micro-paddles or sensors into the tissue culture chamber.
5. The mini-mammalian model of claim 1, wherein an airway is provided on a sidewall of the tissue culture chamber, the airway being in communication with the exterior to provide oxygen to the tissue culture chamber.
6. A mini-mammalian model according to claim 1, wherein there are two kidney culture chambers, one of which is used to culture kidney micro-tissue to simulate kidney metabolic function; the other kidney culture chamber is provided with a dialysis membrane and is communicated with the outside through a separate elimination channel for simulating the elimination of wastes and medicines in the body.
7. Use of a mini-mammalian model as claimed in any one of claims 1-6 for the manufacture of a product for efficacy testing, toxicity testing or drug generation testing.
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| CN202211518830.4A CN115558601B (en) | 2022-11-30 | 2022-11-30 | Mini mammal model and application thereof |
| PCT/CN2023/074875 WO2024113488A1 (en) | 2022-11-30 | 2023-02-08 | Mini mammalian model for drug effect, toxicity and pharmacokinetic detection and use thereof |
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| US20140308688A1 (en) * | 2011-12-08 | 2014-10-16 | Research Triangle Institute | Human emulated response with microfluidic enhanced systems |
| WO2013086502A1 (en) * | 2011-12-09 | 2013-06-13 | President And Fellows Of Harvard College | Organ chips and uses thereof |
| US8940655B2 (en) * | 2012-02-20 | 2015-01-27 | University Of Maryland, College Park | Porous oxide microparticles and composites thereof and methods of making and using same |
| PT2712918E (en) * | 2012-09-28 | 2015-02-17 | Tissuse Gmbh | Multi-organ-chip with improved life time and homoeostasis |
| JP6885942B2 (en) * | 2015-11-23 | 2021-06-16 | インテグリス・インコーポレーテッド | Compositions and Methods for Selectively Etching P-Type Doped polysilicon Compared to Silicon Nitride |
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| WO2019060318A1 (en) * | 2017-09-19 | 2019-03-28 | Cornell Univeristy | Fabrication of a biomimetic platform system and methods of use |
| CN108485975A (en) * | 2018-06-29 | 2018-09-04 | 大连医科大学附属第医院 | Bionical chip kidney |
| CN109400935B (en) * | 2018-09-21 | 2020-03-27 | 福州大学 | Super-hydrophobic surface with bionic pore structure and preparation method thereof |
| KR20210007624A (en) * | 2019-07-12 | 2021-01-20 | 인하대학교 산학협력단 | Modularized multi-organ-on-a-chip system with oxygen controlled parallelized fluid circuit |
| CN111218404A (en) * | 2020-03-31 | 2020-06-02 | 苏州济研生物医药科技有限公司 | Bionic multi-organ chip and preparation method and application thereof |
| CN113862148B (en) * | 2020-06-30 | 2024-08-13 | 再心生物科技有限公司 | Device comprising an organoid chamber and use thereof for culturing, maintaining, monitoring or testing organoids |
| CN111996121A (en) * | 2020-09-30 | 2020-11-27 | 北京大橡科技有限公司 | 3D multi-organ co-culture chip |
| CN112280083B (en) * | 2020-10-29 | 2022-09-06 | 李作林 | Preparation method and application of bionic pitcher plant two-dimensional functional material |
| CN112280678B (en) * | 2020-12-25 | 2021-04-06 | 苏州大学 | Detachable and reusable hydrophobic or super-hydrophobic microfluidic organ chip |
| CN112680348B (en) * | 2020-12-31 | 2022-08-16 | 北京大橡科技有限公司 | Organ model construction method based on organ chip and organ model |
| CN114045218A (en) * | 2021-10-21 | 2022-02-15 | 中国科学院大连化学物理研究所 | Heart/liver/placenta/brain/pancreatic island multi-organ chip |
| CN114317269B (en) * | 2022-03-09 | 2022-05-31 | 苏州大学 | Multi-organ chip and application thereof in drug evaluation |
| CN115558601B (en) * | 2022-11-30 | 2023-06-06 | 苏州大学 | Mini mammal model and application thereof |
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