WO2021114129A1 - 一种用于肿瘤嗜神经侵袭机制研究的体外实验模型 - Google Patents
一种用于肿瘤嗜神经侵袭机制研究的体外实验模型 Download PDFInfo
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- WO2021114129A1 WO2021114129A1 PCT/CN2019/124504 CN2019124504W WO2021114129A1 WO 2021114129 A1 WO2021114129 A1 WO 2021114129A1 CN 2019124504 W CN2019124504 W CN 2019124504W WO 2021114129 A1 WO2021114129 A1 WO 2021114129A1
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- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus
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- the invention belongs to the technical field of life sciences, and specifically relates to an in vitro experimental model for the study of tumor neurophilic invasion mechanism.
- PNI Tumor neurophilic invasion
- squamous cell carcinoma pancreatic cancer
- pancreatic cancer head and neck
- colon and rectum biliary tract and stomach.
- Tumor cells can infiltrate along nerves to a distance beyond the tumor boundary, and the occurrence of nerve invasion is also related to inflammatory reactions and neuropathic pain.
- the lack of effective in vivo or in vitro models has caused the research on the mechanism of neural invasion to fall into a bottleneck. The main mechanism that drives tumor cells to invade the nerves is currently unclear.
- the disadvantage of the prior art is that the tumor cells and the dorsal root ganglion are co-cultured in the same room, and some tumor cells have been in contact with the dorsal root ganglion when the matrigel is injected, and cannot reflect the long-distance infiltration of the tumor during neurophilic invasion in the body. Phenomenon, tumor cells and nerve tissues are mixed in one room, and it is difficult to distinguish whether some induced changes are nerves affected by the metabolism of tumor cells or tumors affected by nerves. Furthermore, culture in well plates, changing the medium to make the cell nutrition short-lived Intermittent, unable to simulate the microenvironment of the continuity of blood transport in the vascular network in the body.
- the purpose of the present invention is to create an in vitro simulation system that is closer to the real microenvironment in the body, and to improve the accuracy and effectiveness of the experimental results.
- the orifice plate culture method is modified, combined with the dual-flow bioreactor dual-chamber culture, one chamber for culturing tumor cells, one chamber for culturing Schwann cells or dorsal root ganglia or other nerve explants, in continuous culture Under the condition of base supply replacement, it can be combined with other new porous hydrogel scaffolds for three-dimensional culture, which highly simulates the real physiological microenvironment in the body.
- the patent of the present invention is mainly to design an effective in vitro model for the study of tumor neurophilic invasion mechanism. Its design is intended to simulate a three-dimensional model of in vitro tissue and cell culture that is highly similar to the in vivo microenvironment, thereby reducing optimization of animal experiments. It is highly in line with the current 3R principles in animal ethics, and can improve the validity of experimental results, bridging the gap between the cellular and molecular level in physiological and pathological and pharmacological research to animal experiments and clinical experiments.
- the technical solution adopted by the present invention is: an in vitro experimental model for the study of tumor neurophilic invasion mechanism, including a first medium supply bottle, a first pump, a first culture chamber, and a first waste liquid
- the collection bottle, the second medium supply bottle, the second pump, the second culture chamber, the second waste liquid collection bottle; the first medium supply bottle, the first pump, the first culture chamber and the first waste liquid collection bottle are connected in sequence ,
- the second culture medium supply bottle, the second pump, the second culture chamber and the second waste liquid collection bottle are connected in sequence.
- a first valve is provided between the first culture chamber and the second culture chamber.
- the chamber and the second culture chamber are connected together, and the first culture chamber is located on the left side of the second culture chamber.
- first culture chamber and the second culture chamber are the same. Both the first culture chamber and the second culture chamber are provided with a microporous membrane.
- the microporous membrane separates the first culture chamber and the second culture chamber into the upper chamber and the chamber.
- the upper chamber and the lower chamber are equipped with two interfaces, one inlet and one outlet, which are respectively an upper inlet, an upper outlet, a lower inlet, and a lower outlet.
- microporous membrane is used to cover Matrigel or to place porous hydrogel scaffolds.
- the first culture chamber is used for culturing tumor cells; the second culture chamber is used for culturing Schwann cells or dorsal root ganglia or other nerve explants.
- the first culture chamber is used for culturing Schwann cells or dorsal root ganglia or other nerve explants; the second culture chamber is used for culturing tumor cells.
- the model can establish three culture modes: 1) Close the first valve, the first culture room will culture tumor cells alone, and the second culture room will culture Schwann cells or dorsal root ganglia or other nerve explants.
- the model is two completely independent three-dimensional culture systems, which can be analyzed and tested separately as a control experiment; the cultures in the first culture room and the second culture room can be exchanged;
- the model can simulate molecular crosstalk between tissues in the body. It can observe the influence of tumor cells on nerve invasion when the tumor cells are in the upstream position, and can detect the induction of tumor cell metabolism on nerves;
- the model can simulate the molecular crosstalk between tissues in the body.
- the influence of tumor cells on nerve invasion can be observed when the tumor cells are in the downstream position, and the induction effect of nerve cell metabolism on tumor cells can be detected.
- the model can be simplified to include the first culture medium supply bottle, the first pump, the first culture chamber, and the second culture chamber.
- Room, the first waste liquid collection bottle, the first culture medium supply bottle, the first pump, the first culture chamber, the second culture chamber, and the first waste liquid collection bottle are connected in sequence; or include the second culture medium supply bottle, the second The pump, the first culture chamber, the second culture chamber, the second waste liquid collection bottle, the second medium supply bottle, the second pump, the first culture room, the second culture room, and the second waste liquid collection bottle are connected in sequence;
- a first valve is provided between the first culture chamber and the second culture chamber, the first culture chamber and the second culture chamber are connected together by the first valve, and the first culture chamber is located on the left side of the second culture chamber .
- Both rooms are equipped with a second valve.
- the main shortcomings of the existing in vitro models are: First, they cannot reflect the long-distance infiltration of tumors along the nerves; Second, they cannot simulate the continuous circulation of blood in the culture microenvironment; Third, it is difficult to find the metabolites of tumors or nerve-related cells against each other. Impact.
- the advantages of the present invention are as follows: 1. Using a dual culture chamber model, one chamber for culturing tumor cells, and the other chamber for culturing nerve Schwann cells or dorsal root ganglia or other nerve explants. Simulating the tandem between tissues in the body, tumor cells invade the nerves at a long distance; 2. The mutual position of the dual culture chambers can be adjusted to control the different effects when the tumor cells are located upstream and downstream of the nerve; 3.
- the present invention is a continuous supply And the system for renewing the culture medium truly simulates the blood circulation in the body, and combined with the use of porous hydrogel scaffolds and other three-dimensional culture methods, it is closer to the real physiological microenvironment in the body, and the cell expression is closer to the real situation in the body. 4.
- the model can be further used to study how to effectively block tumor invasion to nerves in time.
- the model of the present invention simulates a three-dimensional model of in vitro tissue and cell culture that is highly similar to the in vivo microenvironment, thereby reducing optimization of animal experiments, highly conforming to the 3R principle of current animal ethics, and can improve the validity of experimental results, and bridge the physiology The gap between the cellular and molecular level in pathological and pharmacological research to animal experiments and clinical experiments.
- Figure 1 is a schematic diagram of the structure of an in vitro experimental model used in the study of tumor neurophilic invasion mechanism of the present invention
- FIG. 2 is a simplified structural diagram of the in vitro experimental model used for the study of tumor neurophilic invasion mechanism of the present invention
- Fig. 3 is a schematic diagram of the structure of the first culture chamber and the second culture chamber of the present invention.
- the first medium supply bottle 2. The first pump, 3. The first culture chamber, 4. The first waste liquid collection bottle, 5. The second medium supply bottle, 6. The second pump, 7. The second Cultivation chamber, 8. Second waste liquid collection bottle, 9. First valve, 10. Microporous membrane, 11. Upper inlet, 12. Upper outlet, 13. Lower inlet, 14. Lower outlet, 15. Upper chamber, 16 .The lower part of the room, 17. The second valve.
- the in vitro culture model system of the present invention is not limited to the study of the pathological mechanism of tumor neurophilic invasion, but can also be extended to the study of other pathological and pharmacological mechanisms.
- An in vitro experimental model for the study of tumor neurophilic invasion mechanism includes a first medium supply bottle 1, a first pump 2, a first culture chamber 3, a first waste liquid collection bottle 4, and a The second medium supply bottle 5, the second pump 6, the second culture chamber 7, the second waste liquid collection bottle 8; the first medium supply bottle 1, the first pump 2, the first culture chamber 3 and the first waste liquid collection
- the bottle 4 is connected in sequence, the second culture medium supply bottle 5, the second pump 6, the second culture chamber 7 and the second waste liquid collection bottle 8 are connected in sequence, and the first culture chamber 3 and the second culture chamber 7 are arranged between the first culture chamber 3 and the second culture chamber 7.
- a valve 9 connects the first culturing chamber 3 and the second culturing chamber 7 together, and the first culturing chamber 3 is located on the left side of the second culturing chamber 7.
- the first pump 2 transports the culture medium in the first culture medium supply bottle 1 into the first culture chamber 3, the metabolized waste liquid in the first culture chamber 3 is discharged into the first waste liquid collection bottle 4, and the first valve 9 is opened At this time, a part of the culture medium flows through the first culture chamber 3 and then enters the second culture chamber 7.
- the second pump 6 transports the fresh culture medium in the second culture medium supply bottle 5 into the second culture chamber 7.
- the waste liquid metabolized in 7 is discharged into the second waste liquid collection bottle 8.
- the speed of the liquid can be controlled by adjusting the speed of the gear driven by the voltage of the pump.
- the first culturing chamber 3 and the second culturing chamber 8 have the same structure. As shown in FIG. 3, the first culturing chamber 3 and the second culturing chamber 8 are both provided with a microporous membrane 10, which connects the first culturing chamber 3 Separate the upper 15 and lower 16 chambers from the second culture chamber 8.
- the upper 15 and lower 16 chambers are each provided with one inlet and one outlet, which are an upper inlet 11, an upper outlet 12, a lower inlet 13, and a lower outlet 14, respectively.
- the microporous membrane 10 is used to cover the matrigel or to place the porous hydrogel scaffold. In this way, after the first culture chamber 9 and the second culture chamber 7 are connected, the migration of the cells in the vertical direction and the horizontal direction can be simulated at the same time.
- the first culture chamber 3 is used for culturing tumor cells; the second culture chamber 7 is used for culturing Schwann cells or dorsal root ganglia or other nerve explants. Or the first culture chamber 3 is used for culturing Schwann cells or dorsal root ganglia or other nerve explants; the second culture chamber 7 is used for culturing tumor cells.
- Three culture modes can be established for the model: 1) Close the first valve 9, the first culture chamber 3 cultures tumor cells alone, and the second culture chamber 7 cultures Schwann cells or dorsal root ganglia or other nerve explants alone.
- the model is two completely independent three-dimensional culture systems, which can be analyzed and tested separately as a control experiment; the cultures in the first culture chamber 3 and the second culture chamber 7 can be exchanged;
- the model can simulate the molecules between the tissues in the body Crosstalk, you can observe the influence of tumor cells on nerve invasion when the tumor cells are in the upstream position, and detect the induction of tumor cell metabolism on nerves;
- the model can simulate the molecules between the tissues in the body Crosstalk can be used to observe the influence of tumor cells on nerve invasion when the tumor cells are in the downstream position, and to detect the inducing effect of nerve cell metabolism on tumor cells.
- the model can be simplified as shown in Figure 2: including the first medium supply bottle 1, the first pump 2, the first Culture room 3, second culture room 7, first waste liquid collection bottle 4
- the first medium supply bottle 1, first pump 2, first culture room 3, second culture room 7, first waste liquid collection bottle 4 are connected in sequence; or include the second culture medium supply bottle 5, the second pump 6, the first culture chamber 3, the second culture chamber 7, the second waste liquid collection bottle 8, the second culture medium supply bottle 5, the first
- the two pumps 6, the first culturing chamber 3, the second culturing chamber 7, and the second waste liquid collection bottle 8 are connected in sequence; a first valve 9 is provided between the first culturing chamber 3 and the second culturing chamber 7, and the first culturing chamber 3 and the second culture chamber 7 are connected together by a first valve 9, and the first culture chamber 3 is located on the left side of the second culture chamber 7.
- the first pump 2 or the second pump 6 transports the culture medium in the first culture medium supply bottle 1 or the second culture medium supply bottle 5 into the first culture chamber 3 and the second culture chamber 7, and finally the waste liquid flows into the first waste Liquid collection bottle 4 or second waste liquid collection bottle 8.
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Abstract
Description
Claims (9)
- 一种用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,包括第一培养基供应瓶(1)、第一泵(2)、第一培养室(3)、第一废液收集瓶(4)、第二培养基供应瓶(5)、第二泵(6)、第二培养室(7)、第二废液收集瓶(8);所述第一培养基供应瓶(1)、第一泵(2)、第一培养室(3)和第一废液收集瓶(4)依次连接,所述第二培养基供应瓶(5)、第二泵(6)、第二培养室(7)和第二废液收集瓶(8)依次连接,所述第一培养室(3)和第二培养室(7)之间设有第一阀门(9),所述第一培养室(3)和第二培养室(7)通过第一阀门(9)连接在一起,所述第一培养室(3)位于第二培养室(7)的左侧。
- 根据权利要求1所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,所述第一培养室(3)和第二培养室(8)结构相同,所述第一培养室(3)和第二培养室(8)中均设有微孔膜(10),所述微孔膜(10)将第一培养室(3)和第二培养室(8)分隔为室上层(15)和室下层(16),所述室上层(15)和室下层(16)均设有一进一出两个接口,分别为上进口(11)、上出口(12)、下进口(13)、下出口(14)。
- 根据权利要求2所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,所述微孔膜(10)用于覆盖基质胶或者放置多孔水凝胶支架。
- 根据权利要求1所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,所述第一泵(2)与第一培养室(3)之间、第一培养室(3)与第一废液收集瓶(4)之间、第二泵(6)与第二培养室(7)之间以及第二培养室(7)与第二废液收集瓶(8)之间均设有第二阀门(17)。
- 根据权利要求1-4任一所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,所述第一培养室(3)用于培养肿瘤细胞;所述第二培养室(7)用于培养施万细胞或背根神经节或其他神经外植体。
- 根据权利要求1-4任一所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,所述第一培养室(3)用于培养施万细胞或背根神经节或其他神经外植体;所述第二培养室(7)用于培养肿瘤细胞。
- 根据权利要求1-4任一所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,模型可建立三种培养模式:1)关闭第一阀门(9),第一培养室(3)单独培养肿瘤细胞,第二培养室(7)单独培养施万细胞或背根神经节或其他神经外植体,此时模型为两个完全独立的三维培养系统,可单独进行分析检测,作为对照组实验;其中第一培养室(3)和第二培养室(7)内的培养物可调换;2)打开第一阀门(9),第一培养室(3)单独培养肿瘤细胞,第二培养室(7)单独培养施 万细胞或背根神经节或其他神经外植体,此时模型可模拟体内组织间的分子串音,可以观察肿瘤细胞在上游位置时对神经侵袭的影响,可以检测肿瘤细胞代谢对神经的诱导作用;3)打开第一阀门(9),第一培养室(3)单独培养施万细胞或背根神经节或其他神经外植体,第二培养室(7)单独培养肿瘤细胞,此时模型可模拟体内组织间的分子串音,可以观察肿瘤细胞在下游位置时对神经侵袭的影响,可以检测神经细胞代谢对肿瘤细胞的诱导作用。
- 根据权利要求1所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,当不需要区分收集第一培养室(3)和第二培养室(7)的代谢产物进行分析时,该模型可以简化为:包括第一培养基供应瓶(1)、第一泵(2)、第一培养室(3)、第二培养室(7)、第一废液收集瓶(4),所述第一培养基供应瓶(1)、第一泵(2)、第一培养室(3)、第二培养室(7)、第一废液收集瓶(4)依次连接;或包括第二培养基供应瓶(5)、第二泵(6)、第一培养室(3)、第二培养室(7)、第二废液收集瓶(8),所述第二培养基供应瓶(5)、第二泵(6)、第一培养室(3)、第二培养室(7)、第二废液收集瓶(8)依次连接;所述第一培养室(3)和第二培养室(7)之间设有第一阀门(9),所述第一培养室(3)和第二培养室(7)通过第一阀门(9)连接在一起,所述第一培养室(3)位于第二培养室(7)的左侧。
- 根据权利要求8所述的用于肿瘤嗜神经侵袭机制研究的体外实验模型,其特征在于,所述第一泵(2)与第一培养室(3)之间、第二培养室(7)与第一废液收集瓶(4)之间或第二泵(6)与第一培养室(3)之间、第二培养室(7)与第二废液收集瓶(8)之间均设有第二阀门(17)。
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