CN115895895A - Blood vessel series-connected multi-organ chip model and application method thereof - Google Patents
Blood vessel series-connected multi-organ chip model and application method thereof Download PDFInfo
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- CN115895895A CN115895895A CN202310043413.7A CN202310043413A CN115895895A CN 115895895 A CN115895895 A CN 115895895A CN 202310043413 A CN202310043413 A CN 202310043413A CN 115895895 A CN115895895 A CN 115895895A
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Abstract
The invention relates to a multi-organ chip model with blood vessels connected in series and an application method thereof, and the model comprises a multi-organ interconnection chip substrate, organ culture chamber inserts and various organ blood vessel communicating pipelines, wherein a plurality of various organ culture chamber inserting holes are formed in the multi-organ interconnection chip substrate, the organ culture chamber inserts are arranged in the various organ culture chamber inserting holes, the organ culture chamber inserts are sequentially arranged to form a multi-organ simulation system, the multi-organ simulation system comprises at least two organ culture chamber inserts, and the organ culture chamber inserts are sequentially connected through various organ blood vessel communicating channels of the multi-organ interconnection chip substrate. The invention realizes the interaction and the connection among different organs by using the chip and the perfusion technology, is used for simulating various processes of absorption, distribution, metabolism, elimination or immunity of a medicament entering a human body in vitro, and can be used for application research such as organ interaction research, medicament evaluation and the like.
Description
Technical Field
The invention relates to the technical field of organ chip manufacturing, in particular to a blood vessel series-connected multi-organ chip model and an application method thereof.
Background
The pharmacokinetics research relates to various organs, and taking oral drugs as an example, the drugs relate to intestinal absorption, blood distribution, liver metabolism, kidney excretion and other processes in a human body, and sometimes cause adverse reactions of other organs such as skin inflammation and heart infarction. It is reported that a new drug is developed for about 13-15 years on average, costing about 20 billion dollars. However, there is still a very high risk behind the huge time, labor and material costs — up to 90% of the drugs under investigation, which have been tested in animals, fail in clinical human trials due to poor actual efficacy or toxic side effects. The traditional physiological and pathological research technical platform and means for screening and developing the clinical prodrug mainly comprise in-vitro cell culture detection, animal experiments and the like, and have more defects for efficient drug screening.
The multi-organ chip integrates a plurality of organs on one chip to simulate the human body, and can be used for inspecting the comprehensive effect of the medicine on the whole human body. The method realizes cell co-culture of different tissue and organ sources by adopting modes of integration, multiple modules and the like, interconnects the micro-tissues of different modules by utilizing micro-channels or controllable fluid, and simulates the interaction between different organs of a human body and the distribution condition of medicines in the human body. The development of multi-organ chips is continuously developing in the diversified directions of biochemistry imitation, systematization, quantification and immunization.
The invention provides a multi-organ chip of blood vessel series organs, which allows various organs such as intestinal tracts, livers, hearts, kidneys or skins to be integrated through blood vessel structures, can realize each process of absorption, distribution, metabolism, elimination or immunity after in vitro simulation drugs enter a human body, and is helpful for in vitro drug screening tests.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a blood vessel series-connected multi-organ chip model and an application method thereof, wherein the interaction and the connection among different organs are realized by utilizing a chip and a perfusion technology, the model is used for simulating various processes of absorption, distribution, metabolism, elimination or immunity of a medicament entering a human body in vitro, and can be used for application researches such as organ interaction research, medicament evaluation and the like.
The technical scheme adopted by the invention for solving the technical problems is as follows: the utility model provides a multiple organ chip model of blood vessel series connection, can pull out and insert multiple organ interconnection culture chip, including multiple organ interconnection chip base member, organ culture cell inserts and multiple organ blood vessel communicating pipe, multiple organ interconnection chip base member on be provided with a plurality of multiple organ culture cell patchhole, multiple organ culture cell patchhole in all install organ culture cell inserts, organ culture cell inserts arrange in proper order, form multiple organ analog system, include at least two organ culture cell inserts in the multiple organ analog system, the multiple organ blood vessel communicating pipe that loops through multiple organ interconnection chip base member between the organ culture cell inserts connects.
The edge of the multi-organ interconnected chip base body is provided with an organ culture medium perfusion channel communicated with the insertion holes of the multiple organ culture chambers.
The inlet and outlet ports of the organ culture medium perfusion channel are in butt joint with external microfluid pumping equipment, so that a stable liquid flowing environment is provided for organ culture.
Besides culturing cells, organoids or tissues of different organs in the interior of the organ culture chamber insert, vascular cells or lymphatic cells or other ductal epithelial cells are simultaneously cultured on the back side of the organ culture chamber insert, so that different organs are connected through blood vessels or lymphatic vessels.
The bottom of the organ culture chamber insert is provided with a chamber bottom porous membrane.
The porous membrane at the bottom of the chamber allows a plurality of biological or chemical substances such as culture medium liquid, cell factors, cell metabolites, medicines and the like to permeate, thereby realizing the mutual connection among various organs.
An application method of a blood vessel series-connected multi-organ chip model comprises the following specific operation steps:
the method comprises the following steps: chip pretreatment: coating collagen at the bottom of the organ culture insert or on the surface of an internal membrane, wherein the collagen can be Matrigel, type I collagen, rat tail collagen and other natural or high-molecular gels, so that cells are tightly attached to the surface of the membrane in the growth process;
step two: the blood vessel forming method comprises the following steps: 20 to 50. Mu.L of PBS containing 5 to 20% matrigel was added to the blood vessel side of the porous membrane at the bottom of the organ culture chamber, and incubated at room temperature for 1 hour to complete collagen coating on the blood vessel side. Further, the concentration of vascular endothelial cells is adjusted to 0.1 to 1X 10 6 Inoculating each/mL of the cells to the side of a blood vessel of a porous membrane at the bottom of a chamber insert, inverting the cells, culturing the cells in an incubator at 37 ℃ until the cells are attached to the wall, and then culturing the cells in an upright way;
step three: organ culture: selecting a corresponding culture mode according to a desired organ, thereby forming an assembly of multi-organ chips;
step four: injection of drugs for experiments: the injection of oral medicine or intravenous medicine can be selected, and when the medicine is administered, the blood vessel channel of the multi-organ co-culture chip containing blood vessels is continuously circulated or non-circulated and perfused through the inlet of the chip.
The multi-organ chip of the invention can simulate animal organs and plant organs. For animal organs, organs include, but are not limited to, liver, lung, intestine, heart, kidney, fat, eye, ear, nose, pancreatic islet, bone, brain, skin, blood vessel, uterus, periodontal, spleen, placenta, muscle, larynx, bone marrow, and the like. The cells cultured in the cell culture chamber can be single cells or various cells, and can be primary cells, stem cells or cell lines.
Preferably, the first organ culture chamber insert is used for culturing small intestine or intestinal organs, the second culture organ culture chamber insert is used for culturing liver organs, the third culture organ culture chamber insert is used for culturing heart organs, and the fourth culture chamber insert is used for culturing skin organs or kidney organs, which are selected or arranged according to the absorption, distribution, digestion, immunization or excretion of the drug after entering the human body, and the multiple organ co-culture chip can be used for sequentially selecting organs or arranging organs, and can also be used for arranging organs in any mode.
The multi-organ culture chamber is inserted into the interior of the multi-organ culture chamber, except for culturing cells, organoids or tissues of different organs, vascular cells or lymphatic vessel cells or other conduit epithelial cells are simultaneously cultured on the back of the chamber insert, so that different organs are connected through blood vessels or lymphatic vessels, and the connection mode between the organs is better simulated.
Intestinal organ culture mode: regulating intestinal cells to 0.1-5X 10 6 Adding per mL of cell suspension to the non-vascular side of the organ culture chamber insert, putting a conventional cell pore plate for cell adhesion culture, and transferring to a multi-organ co-culture chip containing intestinal tracts for perfusion co-culture;
liver organ culture mode: mixing hepatic cells or liver cancer cells or primary hepatic cells with other non-parenchymal cells in the liver, such as stellate cells, endothelial cells, macrophages and other hepatic cells according to a certain proportion, forming spheroids with uniform size by using various modes of rotary drop culture, low adsorption culture, micropore array culture and the like, inoculating the spheroids into the non-vascular side of the organ culture cell insert according to a certain concentration, and then carrying out perfusion co-culture.
Heart organ culture mode: the method comprises the steps of forming a cardiomyocyte sphere by a three-dimensional printing mode or a spin-drop culture mode, a low adsorption culture mode, a micropore array culture mode and other modes of cardiomyocyte cells formed by differentiation of stem cell iPSCs, culturing the cardiomyocyte sphere in a pore plate until regular beating contraction can occur spontaneously, and transferring the cardiomyocyte sphere to a non-vascular side of an organ culture chamber for perfusion co-culture.
Different organs were cultured with the corresponding medium, and the non-vascular side medium was changed every 2 days.
The invention provides a test mode of oral drugs, and the test mode can be used for carrying out in vitro oral drug pharmacokinetics test experiments.
When the drug is administered, the vascular channels of the multi-organ co-culture chip containing the blood vessels are continuously circulated or non-circulated and perfused through the inlet of the chip. The drug is added to the multi-organ chip through the non-vascular side of the intestinal organ, absorbed through the epithelium of the intestinal organ and enters the vascular channel to realize drug delivery. Different organs can absorb drugs circulating in blood vessels through the vascular endothelial barrier and take up or metabolize or excrete or immunize them.
The administration mode can be single administration, namely, the given medicine is administered according to a certain concentration in a period of time, and intermittent multiple administration or other administration modes can be performed according to the characteristics of different oral medicines.
The invention provides a vein drug test mode, which can be used for carrying out vein drug test experiment in vitro.
In administration, the drug is added to the perfusion medium at a specific concentration, and enters the multi-organ chip system through the chip inlet to perform continuous perfusion in a circulating or non-circulating manner. The administration mode can be single administration, that is, the given drug is administered according to a certain concentration in a period of time, or intermittent multiple administration or other administration modes according to the characteristics of different drugs.
Has the advantages that: the invention relates to a blood vessel series-connected multi-organ chip model and an application method thereof, and the model has the following advantages:
(1) The multi-organ chip provided by the invention can be used for performing interconnected culture on organs with different functions through blood vessels, so that a complex multi-organ test experiment in vitro is realized, and the multi-organ chip has important significance for improving the bionic property of the human body chip and expanding the application range of the human body chip;
(2) The multi-organ chip can be self-assembled into different organs according to requirements to carry out different collocation and assembly, and different experimental purposes such as drug ADME test or drug efficacy evaluation are realized.
Drawings
FIG. 1 is a schematic diagram of a multiple organ interconnect chip according to the present invention;
FIG. 2 is a light field diagram of a porous membrane at the bottom of an organ culture chamber of the vascular endothelial cells of the present invention;
FIG. 3 is a graph of the transmembrane barrier of the intestinal organ after application of Sorafenib in accordance with the present invention;
FIG. 4 is a graph of liver organ drug concentration versus time for Sorafenib drug in accordance with the present invention.
The figure is as follows: 1. the chip comprises a multi-organ interconnection chip substrate, 2, multiple organ culture chamber insertion holes, 3, an organ culture medium perfusion channel, 4, multiple organ blood vessel communication channels, 5, an organ culture chamber insert and 6, a chamber bottom porous filter membrane.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
The embodiment of the invention relates to a multi-organ chip model with serial blood vessels and an application method thereof, as shown in figures 1-2, the model comprises a multi-organ interconnection chip base body 1, organ culture chamber inserts 5 and a plurality of organ blood vessel communicating pipelines 4, wherein the multi-organ interconnection chip base body 1 is provided with a plurality of organ culture chamber inserting holes 2, the organ culture chamber inserts 5 are respectively arranged in the organ culture chamber inserting holes 2, the organ culture chamber inserts 5 are sequentially arranged to form a multi-organ simulation system, the multi-organ simulation system comprises at least two organ culture chamber inserts 5, and the organ culture chamber inserts 5 are sequentially connected through the organ blood vessel communicating pipelines 4 of the multi-organ interconnection chip base body 1.
The edge of the multi-organ interconnected chip matrix 1 is provided with an organ culture medium perfusion channel 3 communicated with the insertion holes 2 of the multiple organ culture chambers.
The inlet and outlet ports of the organ culture medium perfusion channel 3 are butted with external micro-fluid pumping equipment, so that a stable liquid flowing environment is provided for organ culture.
In addition to culturing cells, organoids or tissues of different organs in the interior of the organ culture chamber insert 5, vascular cells or lymphatic cells or other ductal epithelial cells are simultaneously cultured on the back of the organ culture chamber insert 5, thereby connecting the different organs through blood vessels or lymphatic vessels.
The bottom of the organ culture chamber insert 5 is provided with a chamber bottom porous filter membrane 6.
The porous filter membrane 6 at the bottom of the small chamber allows a plurality of biological or chemical substances such as culture medium liquid, cell factors, cell metabolites, medicines and the like to permeate, so that the mutual connection among all organs is realized.
Example 1
A design and manufacturing diagram of a multi-organ interconnected chip with serial blood vessels is shown in figure 1, and the chip comprises a multi-organ culture chip substrate, a cover plate attached to the substrate, a high light transmittance film attached under the substrate, and arrayed organ culture chamber inserts: the multi-organ interconnection chip base 1 includes a plurality of organ culture chamber insertion holes 2, organ culture medium perfusion channels 3, and a plurality of organ blood vessel communication channels 4. Wherein the multiple organ culture chamber insert holes 2 are adapted to receive the organ culture chamber inserts 5 as desired, thereby providing an arbitrary interconnection of the multiple organs. The multiple organ culture chamber inserts 5 may be interconnected by multiple organ vascular communication pathways 4. The organ culture chamber insert is mainly composed of a chamber insert side wall and a chamber bottom porous filter membrane 6.
Example 2
In this example, four major organs for absorption, distribution, metabolism, excretion or immunity after oral administration are combined and arranged, and the four organs are sequentially intestinal, liver, heart, kidney or skin in sequence to form an ADME multi-organ combination. At least one group of such ADME multi-organ combinations is contained on a multi-organ interconnection chip.
The ADME multi-organ combination comprises at least one intestinal organ as the main generator of drug absorption. Prior to inoculation of the intestinal cells, the inside of the organ culture chamber insert, i.e., the non-vascular side, was coated overnight at 4 ℃ with collagen type I at a concentration of 1-100. Mu.g/mL.
The organ culture chamber insert coated with type I collagen was inverted to perform vessel-side coating, 10 to 500. Mu.L of a 1 to 20% PBS solution was added to the vessel side of the porous filter membrane 6 at the bottom of the chamber, and the vessel-side collagen coating was completed by incubating at room temperature for not less than 1 hour.
Regulating the concentration of vascular endothelial cells to 0.1-1 × 10 6 one/mL of the cells were seeded on the vessel side of the porous membrane at the bottom of the chamber insert and cultured in an incubator at 37 ℃ until the cells attached to the wall.
Regulating intestinal cells to 0.1-5X 10 6 Adding the cell suspension per mL into the non-vascular side of a porous membrane 6 at the bottom of an organ culture chamber insert 5, putting a conventional cell pore plate for cell adhesion culture, and transferring the cell suspension to a multi-organ co-culture chip containing an intestinal tract for perfusion co-culture;
liver organ culture mode: mixing hepatic cells or liver cancer cells or primary hepatic cells with other non-parenchymal cells in the liver, such as stellate cells, endothelial cells, macrophages and the like according to a certain proportion, forming spheroids with uniform size by using various modes of rotary drop culture, low adsorption culture, micropore array culture and the like, inoculating the spheroids into the non-vascular side of the organ culture cell insert according to a certain concentration, and then carrying out perfusion co-culture.
Heart organ culture mode: the myocardial cells formed by stem cell IPSC differentiation are three-dimensionally printed, cultured in a rotary drop culture mode, low adsorption culture mode or a micropore array culture mode to form myocardial cell spheres, and the spheres are cultured in a pore plate until the spheres can spontaneously generate regular beating contraction and then transferred to the non-vascular side of an organ culture chamber for perfusion co-culture.
Different organs were cultured with the corresponding culture medium, and the non-vascular side culture medium was replaced every 1 to 3 days.
Example 3
The above intestinal organs were connected to the liver, heart, kidney or skin, and perfusion was performed with endothelial cell culture medium using a diaphragm pump at a flow rate of 0.1 to 1000. Mu.L per minute. Before the drug test, continuous perfusion is carried out for 4 to 72 hours, during which heartbeat test is carried out every 1 to 24 hours.
After 72 hours, 50-600 μ M free fatty acid was added to the vascular endothelial cell culture medium, and high fat induction was performed for 48 hours, during which a heartbeat test was performed every 1-24 hours.
The chip is tested by using an oral liver cancer treatment drug Sorafenib SORA, an intestinal organ culture medium containing 1-30 mu M SORA is prepared and added to the inner side of an intestinal organ culture chamber, and the absorption process of the oral intestinal drug is simulated. During which heartbeat tests were performed every 24 hours, the specific data is shown in fig. 3.
After the first administration, the culture medium of different organs or blood vessels at 1 hour, 4 hours, 24 hours and 48 hours was collected and tested for drug concentration by HPLC-MS, and the specific parameters are shown in FIG. 4.
The blood vessel series multi-organ chip model and the application method thereof provided by the application are introduced in detail, specific examples are applied in the description to explain the principle and the implementation mode of the application, and the description of the above embodiments is only used for helping to understand the method and the core idea of the application; meanwhile, for a person skilled in the art, according to the idea of the present application, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present application.
Claims (7)
1. A multi-organ chip model of blood vessel series connection is characterized in that: including many organs interconnection chip base member (1), organ culture cell insert (5) and multiple organ blood vessel communicating pipe (4), many organs interconnection chip base member (1) on be provided with a plurality of multiple organ culture cell patchhole (2), multiple organ culture cell patchhole (2) in all install organ culture cell insert (5), organ culture cell insert (5) arrange in proper order, form many organs analog system, including two at least organ culture cell inserts (5) in the many organs analog system, loop through multiple organ blood vessel communicating pipe (4) of many organs interconnection chip base member (1) between organ culture cell insert (5) and connect.
2. The model of claim 1, wherein: the edge of the multi-organ interconnected chip base body (1) is provided with an organ culture medium perfusion channel (3) communicated with the insertion holes (2) of the multiple organ culture chambers.
3. The model of claim 2, wherein: the inlet and outlet ports of the organ culture medium perfusion channel (3) are in butt joint with external micro-fluid pumping equipment, so that a stable liquid flowing environment is provided for organ culture.
4. The model of claim 3, wherein: besides culturing cells, organoids or tissues of different organs in the interior of the organ culture chamber insert (5), vascular cells or lymphatic cells or other ductal epithelial cells are simultaneously cultured on the back of the organ culture chamber insert (5), so that different organs are connected through blood vessels or lymphatic vessels.
5. The model of claim 4, wherein: the bottom of the organ culture chamber insert (5) is provided with a chamber bottom porous membrane (6).
6. The model of claim 5, wherein: the porous filter membrane (6) at the bottom of the small chamber allows a plurality of biological or chemical substances such as culture medium liquid, cell factors, cell metabolites, medicines and the like to permeate, so that the mutual connection among all organs is realized.
7. A method of using the serial-connected multi-organ-chip model of claim 6, wherein: the method comprises the following specific operation steps:
the method comprises the following steps: chip pretreatment: coating collagen at the bottom of the organ culture insert or on the surface of an internal membrane, wherein the collagen can be Matrigel, type I collagen, rat tail collagen and other natural or high-molecular gels, so that cells are tightly attached to the surface of the membrane in the growth process;
step two: the blood vessel forming method comprises the following steps: 20 to 50. Mu.L of PBS containing 5 to 20% matrigel was added to the blood vessel side of the porous membrane at the bottom of the organ culture chamber, and incubated at room temperature for 1 hour to complete collagen coating on the blood vessel side. Further, the concentration of vascular endothelial cells is adjusted to 0.1 to 1X 10 6 Inoculating each/mL of the cells to the side of a blood vessel of a porous membrane at the bottom of a chamber insert, inverting the cells, culturing the cells in an incubator at 37 ℃ until the cells are attached to the wall, and then culturing the cells in an upright way;
step three: organ culture: selecting a corresponding culture mode according to a desired organ, thereby forming an assembly of multi-organ chips;
step four: injection of drugs for the experiments: the injection of oral medicine or intravenous medicine can be selected, and when the medicine is administered, the blood vessel channel of the multi-organ co-culture chip containing blood vessels is continuously circulated or non-circulated and perfused through the inlet of the chip.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117660184A (en) * | 2023-12-11 | 2024-03-08 | 上海生物芯片有限公司 | Separated organ chip model and use method and application thereof |
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| CN117660184A (en) * | 2023-12-11 | 2024-03-08 | 上海生物芯片有限公司 | Separated organ chip model and use method and application thereof |
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