CN117417831A - Co-immune culture organoid chip model - Google Patents
Co-immune culture organoid chip model Download PDFInfo
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- CN117417831A CN117417831A CN202311739949.9A CN202311739949A CN117417831A CN 117417831 A CN117417831 A CN 117417831A CN 202311739949 A CN202311739949 A CN 202311739949A CN 117417831 A CN117417831 A CN 117417831A
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Abstract
The invention discloses an immune co-culture organoid chip model, relates to the technical field of organ chips, and mainly solves the problem of too slow immune response during organoid co-culture lesions. The organoid chip model comprises an in-vitro neuron organoid system chip, a control module and a detection scanning system, wherein the control module is arranged to carry out interaction between the organoid system chip and an external monitoring system by adopting a consensus feedback algorithm, the in-vitro neuron organoid system chip is firstly controlled to cultivate various organoids, then the organoids are controlled to secrete and convey immune cells when the organoids generate lesions, and finally the detection scanning system is controlled to display the physiological characteristic change and the immune cell quantity change of each organ on a touch screen, so that the range of a research target is greatly expanded, the chip preparation difficulty is reduced, and the simulation precision of immune co-cultivation is improved.
Description
Technical Field
The invention relates to the technical field of organ chips, in particular to an immune co-culture organoid chip model.
Background
The immune co-culture organoid chip model is an experimental platform based on a microfluidic technology and is used for researching the problems of immune cell interaction, immune regulation mechanism and the like. The model is that a small functional area is built on a chip, so that immune cells can interact in an environment similar to a real biological organoid, and the immune response in a body can be more truly simulated. The immune co-culture organoid chip model can be applied to the fields of cancer, autoimmune diseases and the like, and improves the efficiency and accuracy of related experimental research.
However, this technique also has some drawbacks, such as:
1. study target limitations: since the technology needs to construct a small functional area on a chip, a study object has a certain limitation and is not suitable for researching all types of immune cell interaction and immune regulation mechanisms.
2. The preparation difficulty of the chip is high: the immune co-culture organoid chip model needs to be constructed in a micro-scale mode through a micro-fluidic technology, so that advanced manufacturing technology and equipment are needed, and the chip preparation difficulty is high.
3. The simulation precision is not high: although the immune co-culture organoid chip model can more truly simulate in vivo immune response, the accuracy of the immune co-culture organoid chip model still has a certain limitation, and the immune co-culture organoid chip model cannot completely replace in vivo immune response research.
Disclosure of Invention
Aiming at the defects of the technology, the invention discloses an immune co-culture organoid chip model, which is characterized in that a control module is arranged to perform interaction between organ chips and an external monitoring system by adopting a co-recognition feedback algorithm, firstly, the in-vitro neuron organoid system chip is controlled to culture various organoids, then the organoids are controlled to secrete and convey immune cells when the organoids generate lesions, and finally, a detection scanning system is controlled to display the physiological characteristic change and the immune cell quantity change of each organ on a touch screen, so that the range of a research target is greatly expanded, the chip preparation difficulty is reduced, and the simulation precision of immune co-culture is improved.
In order to achieve the technical effects, the invention adopts the following technical scheme,
an immune co-culture organoid chip model comprises an in-vitro neuron organoid system chip, a detection scanning system and a control module;
the output end of the control module is respectively connected with the output end of the external neuron organoid system chip and the output end of the detection scanning system, the output end of the external neuron organoid system chip is connected with the output end of the detection scanning system, the external neuron organoid system chip comprises a tumor organoid culture area and an immune organoid culture area, the tumor organoid culture area is provided with a cerebroportion, a cardioid, a liver organoid, a gastric organoid, an intestinal organoid and a pulmonary organoid, and the immune organoid culture area is provided with a thymus organoid;
the control module is used for regulating and controlling the working state of each system of the organoid chip model;
the in vitro neuron organoid system chip is used for culturing tumor cells of different organs on the chip, connecting the tumor cells by micro channels and simulating interaction among a plurality of organs in human body;
the detection scanning system is used for detecting the physiological characteristics of the organoid and displaying imaging;
the organoids are used to regulate physiological responses of the various organoids;
The organoids are used to deliver various physiological regulating substances secreted by the organoids to the designated organoids;
liver-like organs are used for pulmonary disease model establishment, drug screening, toxicity testing and tissue reconstruction;
intestinal-like organs are used for pathological research of intestinal cancers;
pulmonary organoids are used in the study of pulmonary diseases and in the treatment of problematic miscellaneous disorders;
the gastric-like organ is used to simulate peristalsis of the stomach and cancer modeling in vivo;
the thymus-like organ is used to secrete lymphocytes-like to form an immune-like system;
the thymus-like organ is respectively connected with the cardioid organ, the liver-like organ, the stomach-like organ, the intestine-like organ and the lung-like organ through micro-channels, the cardioid organ is connected with the lung-like organ, the liver-like organ is connected with the stomach-like organ, and the stomach-like organ is connected with the intestine-like organ.
As a further description of the above technical solution, the in vitro neuron organoid system chip is integrated into a plurality of micro-culture chambers, transfer channels and microfluidic systems, the microfluidic systems regulate, transport and transfer solute concentrations according to gradient changes by fluid shear force and periodically changing mechanical force, the blood comprises hydrochloric acid, glucose, serum proteins and complement factors, the in vitro neuron organoid system chip comprises an upper chip, a sealing film and a lower chip, the upper chip is provided with a main channel, an inlet channel, a tesla micromixer, a collection channel and an outlet channel, the channel inlets of the tesla micromixer are all connected with the first main channel, the inlet channel is connected with the first main channel, the channel outlets of the tesla micromixer are connected with the collection channel, the outlet channel is connected with the collection channel, a hollow area is arranged on the sealing film, the lower chip is provided with an organoid culture chamber, a microporous array layer, the hollow area corresponds to the collection channel, the organoid culture chamber, the microporous array layer and the microporous array layer, the surface of the microporous array is a hydrophobic layer, and the surface of the microporous array is a hydrophobic layer.
As a further description of the above technical scheme, the thymus-like organ is an aggregate of thymic epithelial cells, thymic fibroblasts and thymic dendritic cells, which promote the expression of antigen receptors and the formation of functional subpopulations of T cells under induction of vascular endothelial growth factors, chemokines and cytokines, which are arranged in an open network for contact with other cells in the thymus, and interleukin-7 and transforming growth factor- β secreted by the thymic epithelial cells serve to promote the orderly migration and differentiation of T cells to maturation.
As a further description of the above technical scheme, the brain-like organ is a pluripotent stem cell promoting morphogenesis of cortical neurons, midbrain dopamine neurons and spinal cord motor neuron subtypes under the induction of growth factor BMP, wnt, shh, RA and FGF, and the brain cortex and pituitary are cultivated by serum-free embryoid body suspension; the cardioid organ is a fully functional heart tissue that proliferates and differentiates heart progenitor cells under the combined action of cardiac growth factor Wnt, BMP, FGF, VEGF and TGF-beta.
As a further description of the above technical solution, the liver-like organ is a morphology that non-parenchymal cells and liver parenchymal cells proliferate and differentiate into liver cells and bile duct cells under the co-culture of liver cell growth factors, epidermal growth factors and Wnt, and the liver cells and endothelial cells are induced to be orderly arranged along the electric field direction by simulating radial electric field gradient generated by dielectrophoresis of liver lobular structures, the non-parenchymal cells comprise mesenchymal cells, endothelial cells, astrocytes, adipocytes and dendritic cells, and the vascularized liver tissue is an aggregate of liver cells and endothelial cells formed by a PDMS honeycomb microporous structure array.
As a further description of the above technical solution, the pulmonary organ is formed and differentiated into the morphology of type I alveolar epithelial cells, type II alveolar epithelial cells, mucosal cells, ciliated cells, basal cells, resident cells, macrophages and nerve endings cells by the combined action of fibroblast growth factor, epidermal growth factor, transforming growth factor- β, bone morphogenic protein, wnt, notch signaling molecule, hypoxia-inducible factor and retinoic acid from the epithelial and mesenchymal cells after cell culture and expansion, and the pulmonary organ is provided with two hollow channels on both sides, and the circulatory mechanical strain of the alveolar-capillary interface in the respiratory process is simulated by applying a circulatory vacuum to stretch and deform the PDS porous membrane with cell adhesion.
As a further description of the above technical solution, the intestinal-like organ is morphogenesis in which intestinal epithelial stem cells and intestinal mesenchymal stem cells proliferate and differentiate into absorptive cells, secretory cells and intestinal epithelial tissues under the combined action of Wnt, noggin, EG, B, N2 and Wnt3a, and simulate physiological intestinal peristalsis by applying fluid flow and cyclic mechanical strain force; the gastric-like organ is morphogenesis of intestinal glial cells, mesenchymal cells and epithelial precursor cells for proliferation and differentiation of gastric epithelial cells and secretory cells under the catalysis of hepatocyte growth factors, hepatocyte growth factors and Wnt together, and comprises an acidogenic gland, a smooth muscle layer and functional intestinal neurons for controlling the tissue contraction of an engineering gastric antrum.
As a further description of the above technical solution, the detection scanning system includes a detection module, a scanning module, a processing module and a display module, where the detection module identifies and counts T cells of different types by using flow cytometry and detects the number of T cell molecules by identifying and connecting specific antibodies by using an enzyme-linked immunosorbent assay, the scanning module uses a high resolution LAPS scanner, the high resolution LAPS scanner is composed of a USB-6343 data acquisition card and a SOG-LAPS chip, the processing module is used for processing data and image information, the display module performs man-machine interaction through a touch screen so as to query and observe the number change of T cells and generate a report, and the output ends of the detection module and the scanning module are connected with the input end of the processing module, and the output end of the processing module is connected with the input end of the display module.
As a further description of the above technical solution, the processing module includes a data cleaning unit, a data sorting unit and a data storage unit, where the data cleaning unit fills up the data defect portion by adopting an interpolation algorithm and corrects the abnormal data portion by adopting an abnormality detection algorithm, the data sorting unit sorts the cleaned data according to T cell types by adopting a hybrid clustering algorithm, the data sorting unit sorts the sorted data in order according to numbers, the data storage unit stores the divided data blocks through a distributed metadata base, an output end of the data cleaning unit is connected with an input end of the data sorting unit, an output end of the data sorting unit is connected with an input end of the data sorting unit, and an output end of the data sorting unit is connected with an input end of the data storage unit.
As a further description of the above technical solution, the control module uses a consensus feedback algorithm to perform interaction between each organ chip inside the in vitro neuron organoid system chip and an external monitoring system, where the working method of the consensus feedback algorithm is as follows: firstly, constructing a knowledge graph, collecting interactive substance information among organs of a human body, diseases of the organs, diagnosis and treatment medicine formulas and disease related specialists, then screening related specialists according to the complexity degree of the diseases to establish a group, initiating problems and votes, then collecting votes and insights of the problems by the specialists, converting the votes and insights into nodes and edges in the knowledge graph and weight values connected with the nodes and edges, establishing consensus by converging opinions of the specialists, calculating different consensus metric indexes, and finally outputting a final consensus result according to the result of the consensus metric standard to be used as a conclusion or decision of the task, and carrying out adjustment and enhancement on the knowledge graph according to requirements; the consensus feedback algorithm is essentially that the key features of the actual vector and the final representation vector are dynamically matched to obtain the average score of each key feature:
in the formula (1), m represents the number of key features, n represents the number of confusion classes, The average match score is represented as a result,indicating cumulative score->Representing word sheet matching score,/->A penalty factor is represented, and d represents the blank number of the key feature;
the detailed calculation formula of the penalty factor is:
in the formula (2), the amino acid sequence of the compound,forward index representing final representation vector, +.>Representing the probability of occurrence of the word segment matching score in the forward index of the final representation vector, u representing a random discard coefficient;
the detailed calculation formula of the feature matching score is:
in the formula (3), the amino acid sequence of the compound,representing posterior probability score->Representing the adjustment factor, q represents the forward index of the actual vector.
In summary, by adopting the technical scheme, the invention has the beneficial effects that,
the invention discloses an immune co-culture organoid chip model, which is characterized in that a control module is arranged to carry out interaction between organ chips and an external monitoring system by adopting a consensus feedback algorithm, firstly, an in-vitro neuron organoid system chip is controlled to culture various organoids, then, the organoids are controlled to secrete and convey immune cells when the organoids are diseased, and finally, a detection scanning system is controlled to display the physiological characteristic change and the immune cell number change of each organ on a touch screen, so that the range of a research target is greatly expanded, the chip preparation difficulty is reduced, and the simulation precision of immune co-culture is improved.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings which are required in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings may be obtained from these drawings without inventive faculty for a person skilled in the art,
FIG. 1 is a schematic diagram of the overall architecture of the present invention;
FIG. 2 is a schematic diagram of the chip architecture of an in vitro neuronal organoid system;
FIG. 3 is a schematic diagram of a detection scanning system;
fig. 4 is a schematic view of a processing module structure.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. It should be understood that the description is only illustrative and is not intended to limit the scope of the invention. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the present invention.
1-4, an immune co-culture organoid chip model comprises an in vitro neuron organoid system chip, a detection scanning system and a control module;
the output end of the control module is respectively connected with the output end of the external neuron organoid system chip and the output end of the detection scanning system, the output end of the external neuron organoid system chip is connected with the output end of the detection scanning system, the external neuron organoid system chip comprises a tumor organoid culture area and an immune organoid culture area, the tumor organoid culture area is provided with a cerebroportion, a cardioid, a liver organoid, a gastric organoid, an intestinal organoid and a pulmonary organoid, and the immune organoid culture area is provided with a thymus organoid;
the control module is used for regulating and controlling the working state of each system of the organoid chip model;
the in vitro neuron organoid system chip is used for culturing tumor cells of different organs on the chip, connecting the tumor cells by micro channels and simulating interaction among a plurality of organs in human body;
the detection scanning system is used for detecting the physiological characteristics of the organoid and displaying imaging;
the brain-like organ is used for simulating pathological research of brain tumors;
the organoids are used to deliver various physiological regulating substances secreted by the organoids to the designated organoids;
Liver-like organs are used for pulmonary disease model establishment, drug screening, toxicity testing and tissue reconstruction;
intestinal-like organs are used for pathological research of intestinal cancers;
pulmonary organoids are used in the study of pulmonary diseases and in the treatment of problematic miscellaneous disorders;
the gastric-like organ is used to simulate peristalsis of the stomach and cancer modeling in vivo;
the thymus-like organ is used to secrete lymphocytes-like to form an immune-like system;
the thymus-like organ is respectively connected with the brain-like organ, the cardiac-like organ, the liver-like organ, the stomach-like organ, the intestine-like organ and the lung-like organ through micro-channels, the brain-like organ is connected with the cardiac-like organ, the cardiac-like organ is connected with the lung-like organ, the liver-like organ is connected with the stomach-like organ, and the stomach-like organ is connected with the intestine-like organ.
Example 1
The micro-fluidic system is characterized in that the in-vitro neuron organoid system chip is integrated into a plurality of micro-culture chambers, transfer channels and micro-fluidic systems, the micro-fluidic systems are regulated, transported and transferred through fluid shear force and periodically changing mechanical force, the concentration of solutes is changed according to gradients, the blood comprises hydrochloric acid, glucose, serum proteins and complement factors, the in-vitro neuron organoid system chip comprises an upper chip, a sealing film and a lower chip, the upper chip is provided with a main channel, an inlet channel, a Tesla micromixer, a collecting channel and an outlet channel, the channel inlets of the Tesla micromixer are all connected with the first main channel, the channel outlets of the Tesla micromixer are connected with the collecting channel, the outlet channel is connected with the collecting channel, the sealing film is provided with a hollow area, the lower chip is provided with the organoid culture chambers and a micropore array layer, the hollow area corresponds to the collecting channel, the organoid culture chambers, the substrate layer and the micropore array layer, the surfaces of the micropore array layer except the micropores or the micropore bottom are the super-hydrophobic surface of the micropore array, the surface of the super-hydrophobic surface is the micropore array, and the super-hydrophobic surface of the super-hydrophobic surface is the micropore array is the super-hydrophobic surface.
The working principle of the in-vitro neuron organoid system chip is as follows: the intestinal glial cells, the mesenchymal cells, the epithelial precursor cells, the multifunctional stem cells, the non-parenchymal cells and the hepatic parenchymal cells are placed in different micro-culture chambers, different kinds of functional stem cells are differentiated into various organs through various growth factors and signal paths, various external acting forces and perfusate are formed into blood flow through a microfluidic technology, the medicine is transmitted to a designated pathological organ, and the stress response of the pathological organ under the action of the medicine is simulated.
Example 2
The thymus-like organ is thymus epithelial cells, thymus fibroblasts and thymus dendritic cells aggregate, under the induction condition of vascular endothelial growth factors, chemotactic factors and cytokines, the thymus epithelial cells are arranged into an open network structure so as to contact other cells in thymus, and interleukin-7 and transforming growth factor-beta secreted by the thymus epithelial cells are used for promoting ordered migration and differentiation and maturation of the T cells.
The brain-like organ is that multipotent stem cells promote the morphogenesis of cortical neurons, midbrain dopamine neurons and spinal motor neurons subtype cells under the induction condition of growth factors BMP, wnt, shh, RA and FGF, and the brain cortex and pituitary are cultivated through serum-free embryo-like body suspension; the cardioid organ is a fully functional heart tissue that proliferates and differentiates heart progenitor cells under the combined action of cardiac growth factor Wnt, BMP, FGF, VEGF and TGF-beta.
The working process of the brain-like organ is as follows: the organoid transmits physiological information of a lesion part to the organoid through a nerve system, and the organoid generates corresponding hormone and pheromone to flow through the lesion organoid together through the perfusate; when the test drug is injected, the brain-like organ produces a pheromone for scheduling the test drug and transport to the diseased organ.
The working process of the cardioid organ is as follows: the perfusion liquid is pushed to flow, and sufficient blood-like flow is provided for organs and tissues to supply test drugs, oxygen and various nutrients (such as water, inorganic salts, glucose, proteins, various water-soluble vitamins and the like) and take away metabolic end products (such as carbon dioxide, urea, uric acid and the like) so that cells maintain normal metabolism and functions. Various endocrine hormones and some other humoral factors in the body are also transported to target cells by blood circulation, achieving body fluid regulation in the body and maintaining a relatively constant environment within the body.
In a specific embodiment, when the brain-like organ and the heart-like organ are diseased, the thymus-like organ works as follows:
1. infection stimulation: when the brain-like or heart-like organ is subjected to an infectious stimulus, the body will produce a corresponding immune response, including the removal of pathogens and damaged tissue cells, the release of inflammatory mediators, and the like.
2. Immune cell transfer: during the immune response, T-like lymphocytes will migrate from the thymus-like organ to the brain-like or cardio-like organ, seeking and attacking the infectious agent, and providing antigen-specific cytological memory for subsequent immune responses.
3. Immune cell expansion: in order to cope with acute or chronic infections, the thymus-like organ will try to promote proliferation and expansion of the immune-like cells at an early stage of the immune-like cells. This process is similar to the growth and development of thymic-like cells which proliferate and differentiate into mature T-like lymphocytes.
4. Immune cell activation: in immunocyte-like infected tissues, the thymus-like organ releases a series of cytokines, cytokine-like receptors and immune-like co-stimulatory molecules to activate the immunocyte-like cells, causing them to exhibit optimal enemy recognition and guidance.
5. Immune cell clearance: finally, the occurrence and development of the condition is fundamentally controlled by selective clearance of the infectious pathogen, or by inducing a traitoric immune response to prevent development of the autoimmune response.
Example 3
The thymus-like organ is thymus epithelial cells, thymus fibroblasts and thymus dendritic cells aggregate, under the induction condition of vascular endothelial growth factors, chemotactic factors and cytokines, the thymus epithelial cells are arranged into an open network structure so as to contact other cells in thymus, and interleukin-7 and transforming growth factor-beta secreted by the thymus epithelial cells are used for promoting ordered migration and differentiation and maturation of the T cells.
The liver-like organ is formed by sequentially arranging non-parenchymal cells and liver parenchymal cells along the electric field direction by inducing the liver cells and endothelial cells to proliferate and differentiate into morphology of liver cells and bile duct cells under the co-culture of liver cell growth factors, epidermal growth factors and Wnt through a radial electric field gradient generated by dielectrophoresis simulating liver lobular structures, wherein the non-parenchymal cells comprise mesenchymal cells, endothelial cells, astrocytes, adipocytes and dendritic cells, and the vascularized liver tissue is an aggregate of the liver cells and the endothelial cells formed by a PDMS honeycomb micropore structure array.
The working process of the liver-like organ is as follows: the liver-like organ has the functions of regulating nerves and body fluid to participate in the metabolic process of water and the acid-base balance and mineral metabolism, so as to offset She Kangli urinary hormone behind the hypophysis-like organ; when the liver-like organ is diseased, the liver-like organ sends pheromones to inform the brain-like organ through a nerve-like system, the brain-like organ adjusts the heart-like organ to increase the perfusion volume, and the test medicine is transmitted to the diseased part of the liver-like organ.
In a specific embodiment, the liver-like organ is induced to become cancerous by adding foreign substances or by high-radiation long-time irradiation, and the reaction process of the thymus-like organ is as follows:
1. Cytokine release: the immune cells in the thymus-like organ may release various cytokines such as IL-2, IFN-gamma, TNF-alpha, etc., to activate the immune cells, enhance immune responses and anti-tumor capabilities.
2. T cell activation: the thymus-like organ is taken as a differentiated and mature organ of the T cells, and possibly signals liver cancer cells to recruit the T cells to participate in anti-tumor immune response, and improves the sensitivity and specificity of the T cells to the cancer cells.
3. Immune rejection: liver cancer cells may express some immune antigens, and under the action of immune response, thymus-like organs can produce tumor-specific T cells, which selectively attack and reject cancer cells.
4. Immunomodulation: regulatory T cells (tregs) in the thymus-like organ may exert immunosuppressive effects, inhibiting the growth and metastasis of liver tumors; whereas regulatory B cells (Breg) may promote immune tolerance, reducing unwanted inflammatory responses and tissue damage.
Example 4
The thymus-like organ is thymus epithelial cells, thymus fibroblasts and thymus dendritic cells aggregate, under the induction condition of vascular endothelial growth factors, chemotactic factors and cytokines, the thymus epithelial cells are arranged into an open network structure so as to contact other cells in thymus, and interleukin-7 and transforming growth factor-beta secreted by the thymus epithelial cells are used for promoting ordered migration and differentiation and maturation of the T cells.
The lung-like organ is formed and differentiated into the morphological generation of I-type alveolar epithelial cells, II-type alveolar epithelial cells, mucous membrane cells, cilia cells, basal cells, resident cells, macrophages and nerve peripheral cells by the combined action of fibroblast growth factors, epidermal growth factors, transforming growth factor-beta, bone morphogenetic proteins, wnt, notch signal molecules, hypoxia induction factors and retinoic acid through cell culture and expansion, two hollow channels are formed on two sides of the lung-like organ, and the stretching deformation of a PDS porous membrane with cell adhesion simulates the circulatory mechanical strain of an alveolar-capillary interface in the respiratory process through applying circulating vacuum.
The working process of the pulmonary organ comprises the following steps: the function of the main respiration of the pulmonary organ is actually the specific expression of the dispersing and descending action of the lung qi in the gas exchange process: the lung qi is announced and the turbid qi is exhaled; lung qi failing to descend and clear qi is inhaled. The lung qi has coordinated and orderly dispersing and descending effects, so that the respiration is even and smooth.
In a specific embodiment, when the pulmonary organoid is subjected to a neurological injury, the response of the thymus-like organ is:
1. Immunomodulation: regulatory T cells (tregs) and regulatory B cells (bregs) in the thymus-like organ may exert an immunomodulatory effect, inhibit excessive inflammatory responses and immune injury, and promote regeneration and repair of neural tissue.
2. Cytokine release: immune cells in the thymus-like organ may release various cytokines, such as Nerve Growth Factor (NGF), nerve growth factor (BDNF), etc., to stimulate the growth, differentiation and regeneration of nerve cells.
3. Neuromodulation: neurons and neurotransmitters in the thymus-like organ generally exert a modulating effect on peripheral nervous tissue, such as the release of neurotransmitters such as acetylcholine, dopamine, etc., which promote neuronal activity and nerve regeneration.
4. Regenerating the support: cells in the thymus-like organ may secrete some extracellular matrix, scaffold proteins, etc., forming a vascular-like microtubule that provides support for regrowth and repair of damaged nerve tissue.
Example 5
The thymus-like organ is thymus epithelial cells, thymus fibroblasts and thymus dendritic cells aggregate, under the induction condition of vascular endothelial growth factors, chemotactic factors and cytokines, the thymus epithelial cells are arranged into an open network structure so as to contact other cells in thymus, and interleukin-7 and transforming growth factor-beta secreted by the thymus epithelial cells are used for promoting ordered migration and differentiation and maturation of the T cells.
The intestinal-like organ is morphogenesis of intestinal epithelial stem cells and intestinal mesenchymal stem cells which proliferate and differentiate into absorptive cells, secretory cells and intestinal epithelial tissues under the combined action of Wnt, noggin, EG, B, N2 and Wnt3a, and simulates physiological intestinal peristalsis by applying fluid flow and circulating mechanical strain force; the gastric-like organ is morphogenesis of intestinal glial cells, mesenchymal cells and epithelial precursor cells for proliferation and differentiation of gastric epithelial cells and secretory cells under the catalysis of hepatocyte growth factors, hepatocyte growth factors and Wnt together, and comprises an acidogenic gland, a smooth muscle layer and functional intestinal neurons for controlling the tissue contraction of an engineering gastric antrum.
The working process of the intestinal-like organ is as follows: intestinal epithelial cells in the intestinal-like organ have absorption and secretion functions in the normal intestinal tract. In simulated liquid media, intestinal epithelial cells take up vitamins, minerals, water, micronutrients and the like from the media by simulating the process of intestinal feeding. Microorganisms in an intestinal-like organ provide an energy source, vitamins and some metabolites for the organ. Microorganisms are capable of metabolism using different types of nutrients, producing metabolites of gases (e.g., hydrogen, carbon dioxide, and methane, etc.) and organic acids (e.g., lactic acid, propionic acid, and acetic acid), some of which are absorbed and utilized by intestinal epithelial cells. Immune cells in the intestinal-like organ recognize and attack foreign pathogens, protecting the organ from disease. Meanwhile, immune cells in the intestinal-like organ can also produce different types of cytokines to regulate immune response, and maintain intestinal health and balance. Neurons in the intestinal-like organ can regulate intestinal motility and secretion, influence metabolism and growth of immune cells and intestinal microorganisms, and maintain intestinal homeostasis. At the same time, the neuron can sense the stimulus from the outside, such as machinery, chemistry, temperature and the like, transmit to the brain center and regulate the response of the remote organ.
The working process of the gastric-like organ is as follows: the stomach wall is generally composed of 3 layers of tissue, the inner layer being the mucosal layer, the outer layer being the serosal layer, the middle being the muscular layer consisting of smooth muscle. The muscular layer is divided into 3 layers of oblique line, annular line and longitudinal line according to the different directions of the muscular fibers. The structure of gastric mucosa is complex, most gastric mucosa has gastric glands, but there are also gastric glands free, which are generally of the 3 types: namely the cardiac gland, the pyloric gland and the acid-secreting gland. The former two are distributed in cardiac region and pylorus region respectively, and equally divide mucous. The acid secretion gland mainly exists in mucous membrane of gastric body and gastric fundus, and is straight tubular gland, the acid secretion gland has 3 kinds of cells, namely main cell, parietal cell and mucous cell, except that all the cells can secrete water and inorganic salt, each cell has special secretion; the main cells secrete pepsinogen, the parietal cells secrete hydrochloric acid and endogenous factors, and the mucous cells secrete mucous.
In a specific embodiment, when the external environment or diet is not adapted to the intestinal or gastric organs, and thus the allergic diseases are sudden, the immune response process of the thymus organs is as follows:
1. secretion of antibodies: in the case of allergic diseases, B cells in the thymus-like organ may be activated and begin to secrete IgE antibodies. These IgE antibodies bind to allergen molecules and activate surrounding mast cells and eosinophils.
2. Activation of mast cells: mast cells in the thymus-like organ can also release histamine and other inflammatory mediators through IgE antibodies in response to stimulation by allergen molecules. These inflammatory mediators cause vasodilation and increased vascular permeability in local tissues, causing allergic symptoms such as swelling and pain.
3. Activation of eosinophils: eosinophils in the thymus-like organ are also activated to release histamine, cytokines and other inflammatory mediators in the development of allergic diseases. These inflammatory mediators also lead to vasodilation and increased permeability, promoting local inflammatory responses.
4. Modulating immune responses: regulatory T cells (tregs) and B cells (bregs) in the thymus-like organ may also be involved in the regulation of allergic diseases. These cells can inhibit excessive inflammatory reactions and immune injuries by secreting cytokines, regulating immune reactions, etc., and maintain the balance of the immune system.
Example 6
Further, the detection scanning system comprises a detection module, a scanning module, a processing module and a display module, wherein the detection module adopts flow cytometry to identify and count T cells of different types and adopts an enzyme-linked immunosorbent assay to detect the number of T cell molecules through the identification and connection of specific antibodies, the scanning module adopts a high-resolution LAPS scanner, the high-resolution LAPS scanner is composed of a USB-6343 data acquisition card and an SOG-LAPS chip, the processing module is used for processing data and image information, the display module performs man-machine interaction through a touch screen so as to inquire and observe the number change of the T cells and generate a report, the output ends of the detection module and the scanning module are connected with the input end of the processing module, and the output end of the processing module is connected with the input end of the display module.
In a specific embodiment, the working principle of the high-resolution LAPS scanner is as follows: the LAPS is a field effect based potentiometric sensor that obtains analyte concentration information by detecting sensor surface potentials. The specific adsorption of analytes by the sensitive layer changes the surface potential of the sensor, and this detection mechanism is essentially the same as ISFET. Unlike ISFETs, LAPS devices do not contain PN junctions, whose carriers are mainly from electron-hole pairs created by the intrinsic pathology of semiconductor versus photon. The biggest feature and advantage of the LAPS is that it has a freely and flexibly definable sensing area. With a modulated light beam, a measurement area of arbitrary shape and size can be obtained on the same chip. By means of the optical addressing capability, the single LAPS chip can be used for realizing multi-parameter and multi-site detection, biochemical image detection and other applications.
Further, the processing module comprises a data cleaning unit, a data sorting unit and a data storage unit, wherein the data cleaning unit fills up a data incomplete part by adopting an interpolation algorithm and corrects an abnormal data part by adopting an abnormal detection algorithm, the data sorting unit sorts the cleaned data according to T cell types by adopting a hybrid clustering algorithm, the data sorting unit sorts the sorted data in order according to the number, the data storage unit stores the divided data blocks through a distributed metadata base, the output end of the data cleaning unit is connected with the input end of the data sorting unit, the output end of the data sorting unit is connected with the input end of the data sorting unit, and the output end of the data sorting unit is connected with the input end of the data storage unit.
In a further embodiment, the control module uses a common-knowledge feedback algorithm to perform interaction between each organ chip inside the in-vitro neuron organoid system chip and an external monitoring system, and the working method of the common-knowledge feedback algorithm is as follows: firstly, constructing a knowledge graph, collecting interactive substance information among organs of a human body, diseases of the organs, diagnosis and treatment medicine formulas and disease related specialists, then screening related specialists according to the complexity degree of the diseases to establish a group, initiating problems and votes, then collecting votes and insights of the problems by the specialists, converting the votes and insights into nodes and edges in the knowledge graph and weight values connected with the nodes and edges, establishing consensus by converging opinions of the specialists, calculating different consensus metric indexes, and finally outputting a final consensus result according to the result of the consensus metric standard to be used as a conclusion or decision of the task, and carrying out adjustment and enhancement on the knowledge graph according to requirements; the consensus feedback algorithm is essentially that the key features of the actual vector and the final representation vector are dynamically matched to obtain the average score of each key feature:
in the formula (1), m represents the number of key features, n represents the number of confusion classes, The average match score is represented as a result,indicating cumulative score->Representing word sheet matching score,/->A penalty factor is represented, and d represents the blank number of the key feature;
the detailed calculation formula of the penalty factor is:
in the formula (2), the amino acid sequence of the compound,forward index representing final representation vector, +.>Representing the probability of occurrence of the word segment matching score in the forward index of the final representation vector, u representing a random discard coefficient;
the detailed calculation formula of the feature matching score is:
in the formula (3), the amino acid sequence of the compound,representing posterior probability score->Representing the adjustment factor, q represents the forward index of the actual vector.
In a specific embodiment, in the knowledge graph, knowledge such as a problem, decision factors, a conclusion and the like is expressed in a node and edge form to form a relation graph, a virtual consensus group for processing the problem is selected from professionals in a plurality of related aspects, fields and the like, opinion, insight and analysis results of the expert on the problem are obtained by initiating voting, commenting, asking and discussing and the like, voting analysis results of a plurality of experts are collected and calculated through an algorithm, a final result is determined according to different consensus measurement standards, A is a normal organ, B is a small number of lesion factors are related to C organ and D organ, and when available immune conditions are the same, advantages of the consensus feedback algorithm are confirmed by comparing effects of the knowledge graph, the virtual consensus algorithm and the consensus feedback algorithm, as shown in a table 1.
TABLE 1 consensus feedback list
According to Table 1, the common-knowledge feedback algorithm has better performance at the nodes B and D than the knowledge-graph and virtual common-view algorithm, and the time efficiency is also higher. Compared with the knowledge graph algorithm, the performance of the consensus feedback algorithm on the node B is slightly inferior to that of the knowledge graph algorithm, but the time efficiency is higher, and the method is more suitable for scenes with higher time requirements. Compared with the virtual common view algorithm, the common view feedback algorithm has better performance at each node, higher time efficiency and better solution to the common view problem. Therefore, in the scene, by comparing the effects of different algorithms, a conclusion that the consensus feedback algorithm has advantages in terms of time efficiency and consensus results can be obtained.
The pseudo code form of the consensus feedback algorithm is as follows:
data preparation
function build_knowledge_graph() {
Construction of knowledge graph
knowledge_graph = create_knowledge_graph()
Task, data, expert, problem information/collection
tasks = get_tasks()
data = get_data()
experts = get_experts()
questions = get_questions()
Information such as nodes, relations and the like is added to the knowledge graph
add_nodes_to_graph(knowledge_graph, tasks, data, experts, questions)
}
Expert analysis
function start_vote() {
Construction of virtual consensus groups
virtual_consensus_group = create_vcg(experts)
+/-initiate issue voting and analysis
feedbacks = start_voting(questions, virtual_consensus_group)
}
Data analysis
function analyze_feedback() {
Converting voting analysis results into nodes and edges in a knowledge-graph
feedback_nodes = convert_to_nodes(feedbacks)
Information such as nodes, edges and the like of/(and update knowledge graph
update_knowledge_graph(knowledge_graph, feedback_nodes)
}
Establishment of a// consensus
function build_consensus() {
By aggregating the opinions of the individual experts, a consensus is established and different consensus metrics are calculated
consensus_result = calculate_consensus(knowledge_graph,
virtual_consensus_group)
Output final consensus result according to the result of consensus metric
final_result = output_final_result(consensus_result)
}
Main program of//
function main() {
Data preparation
build_knowledge_graph()
Expert analysis
start_vote()
Data analysis
analyze_feedback()
Establishment of a// consensus
build_consensus()
}
The specific working process of the invention is as follows: the control module receives basic information of pathological organs obtained by the brain-like organs, starts and controls the scanning detection system to perform basic scanning on all the organs according to the basic information to obtain basic pathological images and basic information of non-pathological organs, then controls the thymus-like organs to secrete T-like cells and B-like cells and convey the T-like cells and B-like cells to the pathological organs, starts the scanning detection system again to perform basic scanning on all the organs after 36-48 hours, obtains physiological information of each organoorgan after treatment, and judges the number and types of immune cells generated by the thymus-like organs during immune co-culture in combination with the basic information before treatment, and records and displays the immune cells in multiple terminals.
While specific embodiments of the present invention have been described above, it will be understood by those skilled in the art that these specific embodiments are by way of example only, and that various omissions, substitutions, and changes in the form and details of the methods and systems described above may be made by those skilled in the art without departing from the spirit and scope of the invention. For example, it is within the scope of the present invention to combine the above-described method steps to perform substantially the same function in substantially the same way to achieve substantially the same result. Accordingly, the scope of the invention is limited only by the following claims.
Claims (10)
1. An immune co-culture organoid chip model, characterized in that: the system comprises an in-vitro neuron organoid system chip, a detection scanning system and a control module;
the output end of the control module is respectively connected with the output end of the external neuron organoid system chip and the output end of the detection scanning system, the output end of the external neuron organoid system chip is connected with the output end of the detection scanning system, the external neuron organoid system chip comprises a tumor organoid culture area and an immune organoid culture area, the tumor organoid culture area is provided with a cerebroportion, a cardioid, a liver organoid, a gastric organoid, an intestinal organoid and a pulmonary organoid, and the immune organoid culture area is provided with a thymus organoid;
the control module is used for regulating and controlling the working state of each system of the organoid chip model;
the in vitro neuron organoid system chip is used for culturing tumor cells of different organs on the chip, connecting the tumor cells by micro channels and simulating interaction among a plurality of organs in human body;
the detection scanning system is used for detecting the physiological characteristics of the organoid and displaying imaging;
the brain-like organ is used for simulating pathological research of brain tumors;
the organoids are used to deliver various physiological regulating substances secreted by the organoids to the designated organoids;
Liver-like organs are used for pulmonary disease model establishment, drug screening, toxicity testing and tissue reconstruction;
intestinal-like organs are used for pathological research of intestinal cancers;
pulmonary organoids are used in the study of pulmonary diseases and in the treatment of problematic miscellaneous disorders;
the gastric-like organ is used to simulate peristalsis of the stomach and cancer modeling in vivo;
the thymus-like organ is used to secrete lymphocytes-like to form an immune-like system;
the thymus-like organ is respectively connected with the brain-like organ, the cardiac-like organ, the liver-like organ, the stomach-like organ, the intestine-like organ and the lung-like organ through micro-channels, the brain-like organ is connected with the cardiac-like organ, the cardiac-like organ is connected with the lung-like organ, the liver-like organ is connected with the stomach-like organ, and the stomach-like organ is connected with the intestine-like organ.
2. The immune co-culture organoid chip model of claim 1, wherein: the micro-fluidic system is characterized in that the in-vitro neuron organoid system chip is integrated into a plurality of micro-culture chambers, transfer channels and micro-fluidic systems, the micro-fluidic systems are regulated, transported and transferred through fluid shear force and periodically changing mechanical force, the concentration of solutes is changed according to gradients, the blood comprises hydrochloric acid, glucose, serum proteins and complement factors, the in-vitro neuron organoid system chip comprises an upper chip, a sealing film and a lower chip, the upper chip is provided with a main channel, an inlet channel, a Tesla micromixer, a collecting channel and an outlet channel, the channel inlets of the Tesla micromixer are all connected with the first main channel, the channel outlets of the Tesla micromixer are connected with the collecting channel, the outlet channel is connected with the collecting channel, the sealing film is provided with a hollow area, the lower chip is provided with the organoid culture chambers and a micropore array layer, the hollow area corresponds to the collecting channel, the organoid culture chambers, the substrate layer and the micropore array layer, the surfaces of the micropore array layer except the micropores or the micropore bottom are the super-hydrophobic surface of the micropore array, the surface of the super-hydrophobic surface is the micropore array, and the super-hydrophobic surface of the super-hydrophobic surface is the micropore array is the super-hydrophobic surface.
3. The immune co-culture organoid chip model of claim 1, wherein: the thymus-like organ is thymus epithelial cells, thymus fibroblasts and thymus dendritic cells aggregate, under the induction condition of vascular endothelial growth factors, chemotactic factors and cytokines, the thymus epithelial cells are arranged into an open network structure so as to contact other cells in thymus, and interleukin-7 and transforming growth factor-beta secreted by the thymus epithelial cells are used for promoting ordered migration and differentiation and maturation of the T cells.
4. The immune co-culture organoid chip model of claim 1, wherein: the brain-like organ is that multipotent stem cells promote the morphogenesis of cortical neurons, midbrain dopamine neurons and spinal motor neurons subtype cells under the induction condition of growth factors BMP, wnt, shh, RA and FGF, and the brain cortex and pituitary are cultivated through serum-free embryo-like body suspension; the cardioid organ is a fully functional heart tissue that proliferates and differentiates heart progenitor cells under the combined action of cardiac growth factor Wnt, BMP, FGF, VEGF and TGF-beta.
5. The immune co-culture organoid chip model of claim 1, wherein: the liver-like organ is formed by sequentially arranging non-parenchymal cells and liver parenchymal cells along the electric field direction by inducing the liver cells and endothelial cells to proliferate and differentiate into morphology of liver cells and bile duct cells under the co-culture of liver cell growth factors, epidermal growth factors and Wnt through a radial electric field gradient generated by dielectrophoresis simulating liver lobular structures, wherein the non-parenchymal cells comprise mesenchymal cells, endothelial cells, astrocytes, adipocytes and dendritic cells, and the vascularized liver tissue is an aggregate of the liver cells and the endothelial cells formed by a PDMS honeycomb micropore structure array.
6. The immune co-culture organoid chip model of claim 1, wherein: the lung-like organ is formed and differentiated into the morphological generation of I-type alveolar epithelial cells, II-type alveolar epithelial cells, mucous membrane cells, cilia cells, basal cells, resident cells, macrophages and nerve peripheral cells by the combined action of fibroblast growth factors, epidermal growth factors, transforming growth factor-beta, bone morphogenetic proteins, wnt, notch signal molecules, hypoxia induction factors and retinoic acid through cell culture and expansion, two hollow channels are formed on two sides of the lung-like organ, and the stretching deformation of a PDS porous membrane with cell adhesion simulates the circulatory mechanical strain of an alveolar-capillary interface in the respiratory process through applying circulating vacuum.
7. The immune co-culture organoid chip model of claim 1, wherein: the intestinal-like organ is morphogenesis of intestinal epithelial stem cells and intestinal mesenchymal stem cells which proliferate and differentiate into absorptive cells, secretory cells and intestinal epithelial tissues under the combined action of Wnt, noggin, EG, B, N2 and Wnt3a, and simulates physiological intestinal peristalsis by applying fluid flow and circulating mechanical strain force; the gastric-like organ is morphogenesis of intestinal glial cells, mesenchymal cells and epithelial precursor cells for proliferation and differentiation of gastric epithelial cells and secretory cells under the catalysis of hepatocyte growth factors, hepatocyte growth factors and Wnt together, and comprises an acidogenic gland, a smooth muscle layer and functional intestinal neurons for controlling the tissue contraction of an engineering gastric antrum.
8. The immune co-culture organoid chip model of claim 1, wherein: the detection scanning system comprises a detection module, a scanning module, a processing module and a display module, wherein the detection module adopts a flow cytometry to identify and count T cells of different types and adopts an enzyme-linked immunosorbent assay to detect the number of T cell molecules through the identification and connection of specific antibodies, the scanning module adopts a high-resolution LAPS scanner, the high-resolution LAPS scanner consists of a USB-6343 data acquisition card and an SOG-LAPS chip, the processing module is used for processing data and image information, the display module performs man-machine interaction through a touch screen so as to inquire and observe the number change of the T cells and generate a report, the output ends of the detection module and the scanning module are connected with the input end of the processing module, and the output end of the processing module is connected with the input end of the display module.
9. The immune co-culture organoid chip model of claim 8, wherein: the processing module data cleaning unit fills the data incomplete part by adopting an interpolation algorithm and corrects the abnormal data part by adopting an abnormal detection algorithm, the data sorting unit sorts the cleaned data according to T cell types by adopting a hybrid clustering algorithm, the data sorting unit sorts the sorted data in order according to the number, the data storage unit stores the divided data blocks through a distributed metadata base, the output end of the data cleaning unit is connected with the input end of the data sorting unit, the output end of the data sorting unit is connected with the input end of the data sorting unit, and the output end of the data sorting unit is connected with the input end of the data storage unit.
10. The immune co-culture organoid chip model of claim 1, wherein: the control module adopts a consensus feedback algorithm to carry out interaction between each organ chip in the in-vitro neuron organoid system chip and an external monitoring system, and the working method of the consensus feedback algorithm is as follows: firstly, constructing a knowledge graph, collecting interactive substance information among organs of a human body, diseases of the organs, diagnosis and treatment medicine formulas and disease related specialists, then screening related specialists according to the complexity degree of the diseases to establish a group, initiating problems and votes, then collecting votes and insights of the problems by the specialists, converting the votes and insights into nodes and edges in the knowledge graph and weight values connected with the nodes and edges, establishing consensus by converging opinions of the specialists, calculating different consensus metric indexes, and finally outputting a final consensus result according to the result of the consensus metric standard to be used as a conclusion or decision of the task, and carrying out adjustment and enhancement on the knowledge graph according to requirements; the consensus feedback algorithm is essentially that the key features of the actual vector and the final representation vector are dynamically matched to obtain the average score of each key feature:
In the formula (1), m represents the number of key features, n represents the number of confusion classes,representing average match score, +.>Indicating cumulative score->Representing word sheet matching score,/->A penalty factor is represented, and d represents the blank number of the key feature;
the detailed calculation formula of the penalty factor is:
in the formula (2), the amino acid sequence of the compound,forward index representing final representation vector, +.>Representing the probability of occurrence of the word segment matching score in the forward index of the final representation vector, u representing a random discard coefficient;
the detailed calculation formula of the feature matching score is:
in the formula (3), the amino acid sequence of the compound,representing posterior probability score->Representing the adjustment factor, q represents the forward index of the actual vector.
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| AU2003271042A1 (en) * | 1999-06-25 | 2004-01-22 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | In Vitro Micro-Organs and Uses Related Thereto |
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| AU2003271042A1 (en) * | 1999-06-25 | 2004-01-22 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | In Vitro Micro-Organs and Uses Related Thereto |
| US20150017140A1 (en) * | 2011-12-23 | 2015-01-15 | Anthrogenesis Corporation | Organoids comprising decellularized and repopulated placental vascular scaffold |
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