WO2021180133A1 - 生物反应控制状态胶囊、肠道内容物取样与冷冻保存装置及方法、取样材料在胃肠道内的保存结构与方法 - Google Patents

生物反应控制状态胶囊、肠道内容物取样与冷冻保存装置及方法、取样材料在胃肠道内的保存结构与方法 Download PDF

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WO2021180133A1
WO2021180133A1 PCT/CN2021/080033 CN2021080033W WO2021180133A1 WO 2021180133 A1 WO2021180133 A1 WO 2021180133A1 CN 2021080033 W CN2021080033 W CN 2021080033W WO 2021180133 A1 WO2021180133 A1 WO 2021180133A1
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Prior art keywords
capsule
sampling
water
shell
gastrointestinal tract
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PCT/CN2021/080033
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English (en)
French (fr)
Inventor
张景亮
王磊
肖海
孙丽花
刘书莲
杜沂骏
王超平
介元芬
孙鉴铭
郑晓美
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郑州味千生物技术有限公司
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Priority claimed from CN202010166965.3A external-priority patent/CN111358502B/zh
Priority claimed from CN202010356298.5A external-priority patent/CN111466962B/zh
Priority claimed from CN202010518866.7A external-priority patent/CN111631758A/zh
Application filed by 郑州味千生物技术有限公司 filed Critical 郑州味千生物技术有限公司
Publication of WO2021180133A1 publication Critical patent/WO2021180133A1/zh

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements

Definitions

  • the invention relates to the field of medical technology, in particular to a biological response control state capsule, a device and method for sampling and cryopreservation of intestinal contents, and a storage structure and method for sampling materials in the gastrointestinal tract.
  • the unity of the interaction and influence between the intestinal flora and the human body is called the gut microflora. It is the human body’s largest microecosystem and is closely related to human health and diseases. There have been a large number of studies and evidence in the past decade It shows that the intestinal microecology can regulate brain function. With the proposal and confirmation of the "brain-gut-microflora" axis theory, related research on microecology has involved hypertension, diabetes, intestinal diseases, obesity, cancer, and central nervous system. System diseases.
  • the sampling device will become an ideal tool to realize this project. Furthermore, the function of the sampling device far exceeds the needs and requirements of human intestinal sampling. It is not only meaningful for the distribution of intestinal microbes, but also they The respective by-products, their mutual influence, as well as intestinal secretions, poisons, tumor cells, tumor products, etc. are all important, and it is essential and indispensable to obtain samples directly from the human body.
  • Li Huifeng et al.'s patent Intestinal contents negative pressure automatic sampler (patent number 201711255713.2), set the negative pressure in the capsule, and trigger the sampling switch in the stomach, duodenum, and jejunum
  • the part is sealed with a special film that can be dissolved, and samples are taken after the sealing film is dissolved.
  • These devices rely on changes in the pH value of the intestine or the dissolution of specific compounds by the intestine to trigger sampling.
  • the contents of the gastrointestinal tract have food residues, flora, parasite eggs and other components. To distinguish and obtain these components, it is necessary to rely on the assistance of some medical devices.
  • the flora in the normal human intestine has been regarded as a special organ. There are about a thousand kinds of bacteria in the intestine. The function of most bacteria and the mechanism by which different bacteria work organically are not clear; commonly used probiotic drugs And food is only one or several kinds of bacteria in the intestinal tract; research on bacteria in the intestinal tract has been gradually carried out, especially for infection-related diseases that are ineffective in the treatment of commonly used antibiotics and other drugs.
  • the human intestines provide the most suitable growth environment for microorganisms, once they are sampled, the microorganisms will leave the human intestinal environment, and the growth and death rates of most microorganisms will be greatly changed, which cannot accurately reflect this segment of the gastrointestinal tract.
  • the status of the microbial population of the Tao The current general preservation methods can be cryopreserved and treated with pharmaceuticals. However, such existing methods can be used in vitro, but it is very difficult to target in the digestive tract of humans or other animals. Especially after the capsule is sampled in the intestine, it is a realistic and urgent challenge to keep the contents of the digestive tract stored inside the capsule without changing its activity or the number of flora.
  • the materials sampled from the gastrointestinal tract include not only gastrointestinal microorganisms, but also local proteins, nucleic acids, sugars, lipids and other biologically active substances, including small molecular substances such as hormones in the body. After obtaining it, it must be preserved before it can be used for analysis.
  • the United States, Progenity Company (CN109843182A), mentions many content retention agents in the patent, including the use of glues, surface actives, antibiotics, proteases and so on. However, it does not consider which specific preservative compound has the best effect, nor does it consider which organization method or formula will work better in a disposable sampling capsule without electronic control equipment. Effect.
  • the purpose of the present invention is to provide a biological response control state capsule suitable for animals and humans to solve the above-mentioned problems in the prior art, and effectively solve the problem of using pH changes to trigger sampling, or using electronic mechanical capsules for sampling.
  • a series of problems provide a device and method for sampling and cryopreservation of intestinal contents to solve the above-mentioned problems in the prior art and improve the extraction efficiency and quality of bacteria in the intestinal tract; also provide a storage of sampling materials in the gastrointestinal tract Structure and method to realize the preservation of sampling materials in the gastrointestinal tract.
  • the present invention provides a biological response control state capsule suitable for animals and humans, which includes a capsule shell with a number of one-way valves embedded on the surface of the capsule shell.
  • one, two or more components are used to control pressure changes through physical or chemical reactions or biological growth.
  • one component is squeezed through the gastrointestinal tract to cause a change in its properties, which leads to a change in pressure
  • two or more components are packaged in groups, and the package ruptures after gastrointestinal movement is squeezed to react, or one that participates in the reaction.
  • the component is the gastrointestinal contents.
  • the method of controlling the reaction rate is to wrap multiple microcapsules by the components, each of which has different wall thickness, or different composition and structure, and the rupture speed is different under the squeeze of gastrointestinal movement. Control the reaction speed, or control the speed of the intestinal contents entering the capsule by controlling the permeability of membranes of different thicknesses.
  • a part of the capsule shell is provided with a special capsule wall
  • the special capsule wall is made of a polymer material doped with a water-absorbing material
  • the water-absorbing material may be cellulose, protein or other materials that can form capillary water absorption.
  • the thickness of the capsule wall, the amount of doped water-absorbing material, the method and process of doping will all affect the water absorption speed.
  • the water absorption speed of the doped water-absorbing material determines the speed at which water enters the shell and determines the water as a reactant. Response time and speed.
  • one kind of water-swelling substance or growth-swelling substance can be placed inside or on the inner wall of the capsule shell, or two or more kinds of substances that can react with water and the reaction will cause pressure changes.
  • the inner wall of the capsule shell is provided with a special capsule wall
  • the water-absorbing fibers in the special capsule wall absorb water at a certain speed
  • the inside of the capsule shell is filled with carbon dioxide
  • the capsule wall is coated with alkaline substances and glues.
  • the capillary water absorption speed of cellulose determines the reaction speed of the alkaline substance on the capsule wall and carbon dioxide, and determines the speed of the air pressure drop.
  • the outer wall of the capsule shell is partially surrounded by a gel, the penetration rate of the gel determines the reaction rate, and the gel may contain enzyme molecules.
  • the enzyme molecule refers to an enzyme capable of decomposing the whole or part of the structure of the gel.
  • the water-absorbing material, the water-swelling material, and the gel partially surrounded by the outer wall of the capsule shell mainly include natural hydrophilic products and artificially synthesized water-absorbing polymers, including but not limited to cellulose, protein, starch, agar Sugar, acrylic resins, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, sodium alginate, casein, guar gum, chitosan, gum arabic, xanthan gum, soy protein gum, natural rubber, lanolin, agar polypropylene Amide, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbo resin, polyacrylic acid, sodium polyacrylate, polyacrylate copolymer emulsion, butadiene rubber, styrene butadiene rubber, polyurethane, modified polyurea, low molecular polyethylene Wax, amino alcohol complex titanate.
  • natural hydrophilic products and artificially synthesized water-absorbing polymers including but not limited to cellulose
  • the one-way valve is at least one, and the one-way valve can be a positive pressure and a negative pressure valve, the elastic ball is of an uneven type, and there are two elastic balls.
  • the one-way valve includes two spring cards, and the two spring cards are contacted and sealed by the clamping blocks.
  • four clamping blocks are arranged inside the one-way valve, of which two clamping blocks are connected to the capsule shell by a spring card, and the two clamping blocks are installed in parallel and connected to the capsule shell by a rubber band;
  • the blocking block is triangular, the capsule shell is arc-shaped, and the one-way valve is wide-mouthed.
  • the present invention also provides a device for sampling and cryopreservation of intestinal contents, including a housing, a thermocouple, a piezoelectric module, and a single-chip microcomputer.
  • a number of the piezoelectric modules connected in series or parallel are embedded in the housing, and the housing One end of the body is provided with an electric door assembly, and the other end is equipped with a thermocouple.
  • the piezoelectric module is connected with the single-chip microcomputer, the electric door assembly and the thermocouple.
  • the housing is provided with an inner cavity for storing samples.
  • the door assembly controls the opening and closing of the inner cavity.
  • the shell is contoured to the capsule.
  • the heat absorption side of the thermocouple is arranged in the housing and is connected with a heat absorption net.
  • thermocouple Preferably, a heat dissipation plate is installed on the outer side of the thermocouple, and the outer side of the thermocouple is contoured with the side surface of the housing.
  • the shell includes an inner shell and an outer shell; the outer shell is made of an elastic material, the inner shell is made of a heat-insulating material, or the inner surface of the inner shell is provided with a heat-insulating layer.
  • the piezoelectric module is connected to the electric component, and a rectifier is connected between the piezoelectric module and the electric door component.
  • the piezoelectric module is a piezoelectric ceramic.
  • the electric door assembly includes an electric door and an electric door switch, the electric door switch is connected to the piezoelectric module, and the electric door switch controls the opening and closing of the electric door.
  • the present invention also provides a method for sampling and cryopreservation of intestinal contents, using the above-mentioned intestinal contents sampling and cryopreservation device, the steps are as follows: the piezoelectric module is squeezed to generate electric energy to provide the thermocouple and the electric door assembly; The housing moves to a set position for sampling, the electric door assembly closes the inner cavity of the housing and stores the sample; the thermocouple is energized to cool the inner cavity.
  • the present invention also provides a storage structure for sampling materials in the gastrointestinal tract, including a sampling capsule, the sampling capsule is provided with a package-like structure inside and a drug is wrapped in the package-like structure.
  • the inside of the sampling capsule refers to the inner side wall of the capsule, which is pushed to a central position with a support structure, etc. (that is, the inside of the sampling capsule refers to the space enclosed by the inner side wall of the capsule).
  • the encapsulated structure is composed of a water-absorbing and decomposing material, a semi-permeable membrane material, or a water-impermeable material
  • the medicament is Tris-HCl, disodium ethylenediaminetetraacetic acid (EDTA-2Na) , Sodium Chloride (NaCl), Sodium Dodecyl Sulfate (SDS), Kasone Preservative, Ethanol or Sodium Citrate One or more mixtures.
  • the package-like structure is also made of heat-dissipating materials, and ammonium nitrate or other substances that absorb water or react to lower temperature are also wrapped inside.
  • the present invention also provides a method for preserving sampling materials in the gastrointestinal tract.
  • the method includes the following steps:
  • the capsule shell is set into a material with a certain degree of softness, and the contents will be fully stirred under the squeeze of gastrointestinal movement;
  • the material to be sampled in which water will dissolve various adsorbed and encapsulated materials, and the dissolved material will act on the sampled material to achieve the fixation and preservation of the DNA of the sampled material (put the sampled material and the capsule in the water, the water will The solid components wrapped by the capsule shell, the wrapped structure and the wrapped structure are dissolved to form an aqueous solution, and the aqueous solution acts on the sampling material to realize the fixation and preservation of the DNA of the sampling material).
  • the formula in step A is Tris-HCl buffer, 10-50mM disodium ethylenediaminetetraacetate (EDTA-2Na), 100-150mM sodium chloride ( NaCl) and sodium dodecyl sulfate (SDS) with a mass fraction of 0.1%-0.5% or use ethanol, sodium citrate, EDTA-disodium, Tris-HCl, NaCl and sodium lauryl sulfate or for routine experiments Formula, and the water-absorbing material materials are mainly polysaccharides and proteins, including but not limited to cellulose, gelatin, agarose, gum arabic, xanthan gum, resins, etc., and the packets can be strung together with linear materials.
  • EDTA-2Na disodium ethylenediaminetetraacetate
  • NaCl sodium chloride
  • SDS sodium dodecyl sulfate
  • the water-absorbing material materials are mainly polysaccharides and proteins, including but not limited to cellulose, ge
  • the linear material is fixed on the capsule wall with a certain interval (the linear material has a plurality of fixed points fixedly connected to the capsule wall, and the adjacent fixed points are separated from each other), and the capsule wall It is made of thermal insulation materials, including foamed polyurethane, polystyrene foam, polystyrene board, phenolic foam rubber sponge, polyethylene, polystyrene foam or glass wool, etc.
  • the wrapping part is made of water-absorbing material, which absorbs water The material controls the reaction or participates in the reaction.
  • the storage method in step C is refrigerated storage, and refrigerated storage is a chemically slow endothermic reaction, which mainly uses endothermic chemical reactions or physical changes for the preservation of other biologically active substances, proteins, tumor cells, etc. , It is best that one of the reactants is water, or salt in the gastrointestinal tract or food. At the same time, the endothermic reaction material is placed in a package in the middle of the shell or in multiple packages.
  • the storage method in step C is refrigerated storage, and the refrigerated storage adopts a slow chemical endothermic reaction or a physical endothermic change for refrigeration, and the refrigerated storage is used to store biologically active substances, proteins or For tumor cells, one of the reactants in the slow chemical endothermic reaction is water, gastrointestinal salts or salt in food, and at the same time, the material of the slow chemical endothermic reaction is placed in the package-like structure When the capsule shell is squeezed, the chemically slowly endothermic material reacts, or reacts after the encapsulated structure is dissolved).
  • the biological response control state capsule Compared with the prior art, the biological response control state capsule, the device and method for sampling and cryopreservation of intestinal contents, and the storage structure and method of sampling materials in the gastrointestinal tract of the present invention have the following technical effects:
  • the invention is suitable for the biological reaction control state of animals and humans.
  • the glue structure is scientific and reasonable, safe and convenient to use.
  • Through the fermentation reaction of microorganisms, the growth of organisms, the water swelling of non-toxic substances such as protein and cellulose to the human body, or the human body is preset Determine the pressure-related chemical reaction to achieve the pressure difference, so as to facilitate the opening of the one-way valve of the capsule, realize the sampling of the bacterial colony, and absorb and store it, and control the reaction rate of the gel to realize the extraction of the bacterial colony at different positions , To facilitate medical research.
  • the device and method for sampling and cryopreservation of intestinal contents of the present invention provide a connected piezoelectric module and a thermocouple on the shell.
  • the thermocouple can reduce the temperature in the shell, slow down the reaction of the sample in the shell, and reduce the temperature. Control the temperature range that is conducive to the preservation of the sample.
  • the storage structure and method of the sampling material of the present invention in the gastrointestinal tract have passed experiments, and it is concluded that the sample preserved by the DNA preservation drug or the sample preserved by the chemical reaction freezing method, after 8 hours of preservation, and direct sampling immediately refrigerator refrigeration
  • the samples of 8 hours have basically the same flora and structure, which proves that the preservation effect of the preservation method in the body is stable and reliable, and can reach the preservation level of the refrigerator. This is of great significance for the materials still in the intestinal tract after sampling that cannot be sent for inspection in time, and for preserving the stability of the flora and structure, and for the detection and inspection in the later stage of sampling.
  • Fig. 1 is a schematic diagram of the structure of the capsule for controlling the biological response of animals and humans according to the present invention
  • FIG. 2 is a schematic diagram of the structure of the connection relationship between the capsule wall, the gel and the capsule shell in the capsule of the present invention, which is suitable for the biological reaction control state of animals and humans;
  • Figure 3 is a schematic diagram of the connection relationship between the spring card and the block in the capsule of the biological response control state applicable to animals and humans according to the present invention
  • FIG. 4 is a schematic diagram of the structure of the connection relationship between the spring card, the block and the rubber band in the biological response control state capsule of the present invention applicable to animals and humans;
  • Figure 5 is a schematic diagram of the structure of the device for sampling and cryopreservation of intestinal contents according to the present invention.
  • Figure 6 is a schematic circuit diagram of the device for sampling and cryopreservation of intestinal contents of the present invention.
  • Fig. 7 is a graph showing the temperature change of the inner cavity of the intestinal contents sampling and cryopreservation device of the present invention after sampling of the shell;
  • Capsules for biological response control of animals and humans; 1. Capsule shell; 2. One-way valve; 3. Capsule wall; 4. Absorbent fiber; 5. Carbon dioxide; 6. Elastic ball; 7. Spring Card; 8, card block; 9, rubber band; 10, gel; 200, intestinal contents sampling and cryopreservation device; 11. elastic shell; 12, single-chip microcomputer; 13, electric door switch; 14, metal heat dissipation shell; 15. Thermocouple; 16. Metal heat absorption net; 17, Insulation inner shell; 18. Piezoelectric module; 19. Shell; sx represents the temperature change curve in the shell when the thermocouple is not used; xx represents the shell when the thermocouple is used The temperature change curve in the body.
  • the purpose of the present invention is to provide a biological response control state capsule suitable for animals and humans to solve the above-mentioned problems in the prior art, and effectively solve the problem of using pH changes to trigger sampling, or using electronic mechanical capsules for sampling.
  • Series of problems Provide a device and method for sampling and cryopreservation of intestinal contents to solve the above-mentioned problems in the prior art and improve the extraction efficiency and quality of bacteria in the intestinal tract.
  • this embodiment provides a biological response control state capsule 100 suitable for animals and humans.
  • 1 is an arc
  • the one-way valve 2 is a wide-mouth type.
  • one-way valve 2 is at least one, and the one-way valve 2 can be a positive pressure and a negative pressure valve, which is convenient for use in different environments, and is convenient for drugs and bacteria. Discharge and absorption of the group;
  • One component or multiple components are squeezed through the gastrointestinal tract and cause changes in their properties, leading to pressure changes. Multiple components are grouped and packaged. After gastrointestinal movement is squeezed, the package ruptures and reacts. A component that participates in the reaction. It can be the gastrointestinal contents, the method of controlling the reaction rate, by wrapping multiple capsules with components, each of which has different wall thicknesses, so that the rupture rate is different, so as to control the reaction rate.
  • one set of packages is sealed with carbonate substances, the other group is directly put into acid substances, the thickness of the package is controlled, and a series of capsules are made according to the thickness of the microcapsules inside the package; when the sampling capsule is taken orally into the human stomach After entering the intestine, under the squeezing action of gastrointestinal movement, after a certain period of time, the microcapsules rupture, the acid and carbonate react to produce carbon dioxide, which increases the pressure in the capsule and opens the one-way valve. Subsequently, during gastrointestinal movement, the substance in the gastrointestinal tract is squeezed into the capsule. After the substance in the gastrointestinal tract enters the capsule, its water will dissolve the spring card fixing glue.
  • the fixing glue is composed of glues that are easy to absorb water, such as carrageenan, xanthan gum, and gelatin. Next, the capsule mouth is closed until it is discharged from the body.
  • this embodiment provides a biological response control state capsule 100 suitable for animals and humans.
  • 2 includes two spring cards 7, the two spring cards 7 are contacted and sealed by the clamping block 8, and the clamping block 8 is triangular, the capsule shell 1 is arc-shaped, and the one-way valve 2 is a wide-mouth type in production.
  • the gel 10 there is a gel 10 on the outer wall of the capsule shell 1.
  • Gelatin can be used for the gel 10.
  • the water absorption and penetration speed of the gel 10 determines the reaction speed.
  • the gel 10 contains enzyme molecules and uses proteases. Under the conditions of the gastrointestinal environment temperature, this gelatinous substance may liquefy quickly, and over time, the liquefaction will cause the membrane to be dissolved, which is equivalent to opening the valve, and the contents of the intestine can be squeezed in. .
  • the block 8 slowly absorbs water and becomes soft, and is slowly closed under the action of the spring 7.
  • this embodiment provides a biological response control state capsule 100 suitable for animals and humans.
  • 2 includes two spring cards 7, the two spring cards 7 are contacted and sealed by the clamping block 8, and the clamping block 8 is triangular, the capsule shell 1 is arc-shaped, and the one-way valve 2 is a wide-mouth type in production.
  • the inner wall of the capsule shell 1 is provided with a capsule wall 3, the capsule wall 3 is doped with cellulose and made of pressed cellulose and other materials that can not be digested and can absorb water through capillary phenomenon, and the size and thickness of the establishment will determine the water absorption
  • the speed of water absorption determines the reaction speed, growth speed and pressure change speed.
  • dry yeast and glucose are added inside.
  • the yeast has Oxygen or anaerobic growth produces carbon dioxide.
  • the one-way valve 2 opens, and the contents of the intestine can be absorbed in.
  • Absorbing fibers 4 are connected to the inner wall of the capsule shell 1 below the one-way valve 2.
  • the inside of the capsule shell 1 is filled with carbon dioxide 5, and the bottom end of the capsule shell 1 is provided with a number of elastic balls 6.
  • the elastic balls 6 are non-uniform, and there are two elastic balls 6 so as to facilitate normal bounce.
  • this embodiment provides a biological response control state capsule 100 suitable for animals and humans.
  • Four clamping blocks 8 are arranged inside, of which two clamping blocks 8 are connected to the capsule housing 1 through a spring card 7, and two clamping blocks 8 are installed in parallel, and are connected to the capsule housing 1 through a rubber band 9, and the clamping block 8 It is triangular, the capsule shell 1 is arc-shaped, and the one-way valve 2 is wide-mouthed.
  • there is at least one one-way valve 2 and the one-way valve 2 can be a positive pressure and a negative pressure valve, so as to facilitate different environments Use, so as to facilitate the excretion of drugs and the absorption of flora;
  • the two components control the pressure change through physical and chemical reactions; and the inner wall of the capsule shell 1 is provided with a capsule wall 3, which is made of water-absorbing material.
  • the water-absorbing material is made of cellulose and other non-digestible materials. It is made of a material that absorbs water through capillary phenomenon, and the size and thickness of the capsule wall will determine the speed of water absorption.
  • the capsule is filled with carbon dioxide or ammonia gas, and the inner wall of the capsule shell 1 is sealed with a glue.
  • the gas is consumed by a rapid reaction, and the internal gas pressure drops.
  • the one-way valve 2 opens, and the contents of the intestine can be absorbed in, and will be under the one-way valve 2.
  • the inner wall of the capsule shell 1 is connected with absorbent fibers 4, the inside of the capsule shell 1 is filled with carbon dioxide 5, and the bottom end of the capsule shell 1 is provided with a number of elastic balls 6.
  • the elastic balls 6 are of uneven type, and the elastic balls 6 are provided with Two, so as to facilitate normal bounce.
  • this embodiment provides a biological response control state capsule 100 suitable for animals and humans.
  • Four clamping blocks 8 are arranged inside, of which two clamping blocks 8 are connected to the capsule housing 1 through a spring card 7, and two clamping blocks 8 are installed in parallel, and are connected to the capsule housing 1 through a rubber band 9, and the clamping block 8 It is triangular, the capsule shell 1 is arc-shaped, and the one-way valve 2 is wide-mouthed.
  • there is at least one one-way valve 2 and the one-way valve 2 can be a positive pressure and a negative pressure valve, so as to facilitate different environments Use, so as to facilitate the excretion of drugs and the absorption of flora;
  • the block 8 can be composed of a special capsule wall 3 or a water-permeable gel.
  • the special capsule wall 3 is doped with cellulose and pressed.
  • the block 8 is filled with water-absorbing substances, preferably composed of cellulose, protein, and starch. ,
  • the size and thickness of the special sac wall or water-permeable gel will determine the speed of water absorption, and the speed of water absorption determines the expansion speed, expand to one side and pull the spring card 7 or rubber band 9, the one-way valve 2 opens, and the contents of the intestine It can be absorbed; if the sac wall ruptures, the valve closes.
  • the working principle and use process of the present invention before use, the patient performs normal physical examination and diet according to the doctor's requirements, and then takes samples according to the needs of the patient, and swallows the capsule shell 1 into the body, and the surface of the capsule shell 1 is embedded with a unidirectional Valve 2, when the one-way valve 2 is under pressure, it automatically opens.
  • the one-way valve 2 By excluding carbon dioxide 5, the colonies that need to be collected in the body enter the capsule shell 1 through the one-way valve 2 opened due to the pressure difference, and the capsule shell 1 Absorbent fibers 4 are connected to the inner wall to facilitate the absorption of collected colonies, or dissolve through gel 10 to discharge the medicine in the capsule shell 1 for collection, and finally squeeze the food to leave the collection area.
  • a one-way valve 2 As the pressure difference becomes smaller, the one-way valve 2 is closed, and finally discharged through the body to achieve normal colony collection.
  • Purpose Put the autosampler into the simulated gastrointestinal device to obtain the time and area data of valve opening and closing.
  • Capsule manufacturing method description Choose one of the size of the capsules of 00, 0, and 1, the shell is made of biocompatible materials such as polylactic acid, polyacrylonitrile, polytetrafluoroethylene, and the key pressure expansion and rupture area is 1mm, There are 2 data in 2mm.
  • the thickness of the capsule shell is 1-8mm, and the area of cellulose fabric is 0.01, 0.05, 0.1, 0.15 square centimeters.
  • the inner fiber cloth of the cellulose fabric is wrapped with alkaline substances such as calcium oxide and magnesium oxide powder.
  • the interior is filled with carbon dioxide gas.
  • Use gelatin or other glues as a spring to seal the blocking block, and when it is dissolved, begin to seal.
  • TIM TNO Intestinal Model
  • TIM-1 stomach and small intestine simulator
  • TIM-2 large intestine simulator
  • This experiment uses TIM-1 to obtain the time and area data of valve opening and closing.
  • the sampler is made according to the above method, divided into 4 groups, 5 in each group, size 0 capsules, the shell is made of polylactic acid biocompatible material, the key pressure expansion and rupture area is 1mm, so that it can resist 0.1-0.3 Double the atmospheric pressure.
  • the thickness of the capsule shell is expected to be 5mm.
  • the area of the cellulose fabric is 0.01, 0.05, 0.1, 0.15 square centimeters.
  • the inner fiber cloth of the cellulose fabric is wrapped with alkaline substances such as calcium oxide + magnesium oxide powder, totaling 0.1 grams, which absorbs water. After that, the reaction started, and gelatin was used as a spring to seal the block. When it was dissolved, the seal was started.
  • each sampling time is 20-30 minutes. According to observations, within 10 minutes, each capsule has been filled with sampled contents; The device basically meets the requirements of gastrointestinal sampling.
  • this embodiment also provides a device 200 for sampling and cryopreservation of intestinal contents, which includes a housing 19, a thermocouple 15, a piezoelectric module 18 and a single-chip microcomputer 12.
  • the electric module is embedded in the housing 19, one end of the housing 19 is provided with an electric door assembly, and the other end is installed with a thermocouple 15.
  • the piezoelectric module 18 is connected with the single chip microcomputer 12, the electric door assembly and the thermocouple 15, and the housing 19 is provided for storage In the inner cavity of the sample, the single-chip microcomputer 12 controls the opening and closing of the inner cavity through the electric door assembly.
  • the piezoelectric module 18 embedded in the housing 19 is electrically connected to the single chip microcomputer 12, the electric door assembly and the thermocouple 15, and the outer surface of the piezoelectric module 18 is provided with an insulating layer or an insulating film.
  • the peristalsis of the intestine drives the housing 19 to move, and the piezoelectric module 18 is squeezed to generate electric energy to provide the thermocouple 15 and the electric door assembly; the housing 19 moves to the set position, and the electric door assembly closes the inner cavity of the housing 19;
  • the single-chip microcomputer 12 controls the thermocouple 15 to be energized.
  • thermocouple 15 absorbs the heat of the inner cavity, and the heat release side of the thermocouple 15 releases the heat into the intestine.
  • the temperature of the absorbed inner cavity drops to the set point.
  • the temperature is set, the sample inside is cooled and stored, and the housing 19 is taken out at the same time.
  • the housing 19 is shaped like a capsule.
  • the two ends of the housing 19 are arc-shaped, and the resistance received during the movement in the intestinal tract is small, and damage to the intestinal tract is also avoided.
  • the two ends of the shell 19 are arc-shaped, with a smooth transition in the middle.
  • thermocouple 15 the heat absorption side of the thermocouple 15 is arranged in the housing 19 and is connected with a heat absorption net.
  • the heat absorption net is a metal heat absorption net 16, which is provided with sequential or multilayer metal heat absorption nets 16, connected to the heat absorption side of the thermocouple 15, and transfers the temperature of the inner cavity to the heat absorption side of the thermocouple 15 through the metal heat absorption net 16 and the thermocouple.
  • frozen substances such as dry ice and calcium hydroxide, and low-temperature saturated salt solutions (sodium chloride, sodium sulfate, etc.) are pre-installed in the housing 19, and heat-conductive materials are used.
  • the material is a copper sheet) sealed into a thin sheet, instead of the metal heat absorption net 16, absorbs the heat of the inner cavity, so as to realize the cooling and storage of the sample.
  • thermocouple 15 is installed on the outside of the thermocouple 15, and the outside of the thermocouple 15 and the side surface of the housing 19 are profiled.
  • the outer side of the thermocouple 15 and the housing 19 are on the same arc surface.
  • the heat dissipation plate is a metal heat dissipation shell 14.
  • the metal heat dissipation shell 14 accelerates the heat dissipation efficiency of the heat radiation side of the thermocouple 15 so that the temperature of the inner cavity will not be affected by the intestinal tract.
  • the outer side of the thermocouple 15 is profiled with the side surface of the housing 19, and the resistance of the housing 19 is not increased.
  • the shell 19 includes an inner shell 17 and an outer shell 11; the outer shell 11 is made of elastic material, the inner shell 17 is made of heat insulating material, or the inner surface of the inner shell 17 is provided with a heat preservation layer .
  • the inner surface of the inner shell 17 is provided with a thermal insulation layer
  • the outer shell 11 made of an elastic material is an elastic shell
  • the elastic material is silica gel or a thermoplastic elastomer (TPE) material.
  • the elastic material is TPE elastomer material.
  • TPE elastomer material Compared with silica gel, TPE elastomer material has the same hardness and elasticity as silica gel, but TPE elastomer material can be injected or extruded quickly, and can be 100% recycled. use.
  • the inner shell 17 is made of heat-insulating material to make a heat-insulating inner shell.
  • the heat-insulating material can be any one or more combinations of polystyrene foam, polyurethane foam or phenolic foam.
  • Thermal insulation materials include, but are not limited to, the aforementioned polystyrene foam, polyurethane foam or phenolic foam.
  • the piezoelectric module 18 is connected to the electric door assembly, and a rectifier is connected between the piezoelectric module and the electric door assembly.
  • the rectifier converts the alternating current of the piezoelectric module 18 into direct current and supplies it to the electric door assembly and the thermocouple 15.
  • the electric door assembly includes an electric door switch 13 and an electric door.
  • the electric door switch 13 is connected with a single-chip microcomputer.
  • a clock circuit is integrated on the single-chip 12. The clock circuit controls the electric door switch 13 to be energized. After the electric door switch 13 is energized, the electric door is closed.
  • the clock circuit can be DS1302 or DS1307.
  • DS1302 is a circuit with trickle current charging capability.
  • the main feature is the use of serial data transmission, which can provide programmable charging function for the power failure protection power supply, and the charging function can be turned off.
  • the piezoelectric module 18 is a piezoelectric ceramic.
  • the piezoelectric ceramics 8 can be barium titanate, lead zirconate titanate binary or ternary or multi-element piezoelectric ceramics; preferably multi-element piezoelectric ceramics, piezoelectric ceramics are composed of quartz crystal, barium titanate, Lead zirconate titanate, polyvinylidene fluoride, lithium niobium oxide, zinc oxide, cadmium sulfide vinyl dicyanide, vinyl acetate, isobutylene, methyl methacrylate, vinyl benzoate are produced by copolymerization.
  • the piezoelectric ceramic 8 is connected with the thermocouple and the electric door assembly to provide electrical energy for the thermocouple and the electric door assembly.
  • This embodiment also provides a method for sampling and cryopreservation of intestinal contents.
  • the device 200 for sampling and cryopreservation of intestinal contents is used. The steps are as follows: intestinal peristalsis drives the housing 19 to move, and the piezoelectric module is squeezed. The generated electric energy is supplied to the thermocouple and the electric door assembly; the housing 19 moves to a set position for sampling, the electric door assembly closes the inner cavity of the housing 19 and stores the sample; the thermocouple is energized to cool the inner cavity, and the housing 19 is taken out.
  • the peristalsis of the intestine drives the housing 19 to move, and the piezoelectric module 18 is squeezed to generate electrical energy to provide the thermocouple 15 and the electric door assembly; the housing 19 moves to the set position, and the electric door assembly closes the inside of the housing 19 Cavity; realize access to the sample in the intestine, the single-chip microcomputer 12 controls the thermocouple 15 to be energized, the heat absorption side of the thermocouple 15 absorbs the heat of the inner cavity, and the heat release side of the thermocouple 15 releases the heat into the intestine, and the temperature of the inner cavity is absorbed The temperature is lowered to the set temperature, and the samples inside are cooled and stored.
  • sx represents the temperature change curve in the housing 19 when the thermocouple is not used;
  • xx represents the temperature change curve in the housing 19 when the thermocouple is used.
  • Two sets of shells 19 were used for comparison experiments, namely, the shell without thermocouple 19 and the shell with thermocouple 19, respectively. Put the shell without thermocouple 19 and the shell 19 with thermocouple into the simulated gastrointestinal tract.
  • the large intestine simulator is selected as the simulated gastrointestinal device.
  • each group has five shells 19; the ambient temperature is 25 degrees, and the temperature sensor probes are placed inside the two types of shells 19 to sample, without affecting the operation
  • record the temperature data in the shell 19 set the sampling time point of the shell 19 at the beginning of 4 hours, and the total experiment time is 12 hours.
  • the control group is not connected with a thermocouple, and other conditions are the same.
  • the experimental results are shown in sx and xx in Figure 7.
  • the thermocouple can reduce the temperature in the shell 19, slow down the reaction in the shell 19, and finally control the temperature between 1-5 degrees Celsius, which is beneficial to the sample save.
  • the working principle of the present invention the peristalsis of the intestines drives the housing 19 to move, while the piezoelectric module 18 is squeezed to generate electric energy to provide the thermocouple 15 and the electric door assembly; the housing 19 moves to the set position, and the electric door assembly closes the housing
  • the inner cavity of 19 realizes the access of samples in the intestine, the single-chip microcomputer 12 controls the thermocouple 15 to be energized, the heat-absorbing side of the thermocouple 15 absorbs the heat of the inner cavity, and the heat-emitting side of the thermocouple 15 releases the heat into the intestine, which is absorbed.
  • the temperature of the inner cavity drops to the set temperature, and the samples inside are cooled and stored.
  • This embodiment provides a storage structure for sampling materials in the gastrointestinal tract, including a sampling capsule.
  • the sampling capsule is provided with a package-like structure and a drug is wrapped in the package-like structure.
  • the structure is pushed to the central position, etc.
  • the wrapped structure is composed of water-absorbing and decomposing material, semi-permeable membrane material or impermeable material, and the medicine is tris-hydroxymethyl aminomethane (Tris-HCl), disodium ethylenediaminetetraacetic acid (EDTA- 2Na), sodium chloride (NaCl), sodium dodecyl sulfate (SDS), kasone preservative, ethanol or sodium citrate one or more of the mixture, the wrapped structure is also made of heat-dissipating materials, And the inside is also wrapped with ammonium nitrate, or other substances that absorb water or react to lower the temperature.
  • Tris-HCl tris-hydroxymethyl aminomethane
  • EDTA- 2Na disodium
  • This embodiment also provides a method for storing sampling materials in the gastrointestinal tract, and the method includes the following steps:
  • the capsule shell is set into a material with a certain degree of softness, and the contents will be fully stirred under the squeeze of gastrointestinal movement;
  • the material to be sampled in which water will dissolve various adsorbed and encapsulated materials, and the dissolved material will act on the sampled material to realize the fixation and preservation of the DNA of the sampled material.
  • step A Tris-HCl buffer, 10-50mM disodium ethylenediaminetetraacetate (EDTA-2Na), 100-150mM sodium chloride (NaCl) and mass fraction 0.1%-0.5% sodium dodecyl sulfate (SDS) or use of ethanol, sodium citrate, EDTA-disodium, Tris-HCl, NaCl and sodium lauryl sulfate or conventional experimental formulations, and water-absorbing substances
  • the materials are mainly polysaccharides and proteins, including but not limited to cellulose, gelatin, agarose, acacia, xanthan gum, resins, etc.
  • the packets can be strung together by linear materials and fixed by linear materials
  • the shell wall is made of thermal insulation material, including foamed polyurethane, polystyrene foam, polystyrene board, phenolic foam rubber sponge, polyethylene, polystyrene foam or glass wool
  • the wrapping part is made of water-absorbing material, and the water-absorbing material controls the reaction or participates in the reaction.
  • the storage method in step C is refrigerated storage, and refrigerated storage is a chemical slow endothermic reaction. It mainly uses endothermic chemical reactions or physical changes for the preservation of other biologically active substances, proteins, tumor cells, etc., preferably one of them
  • the reactant is water, or salt in the gastrointestinal tract or food.
  • the endothermic material is placed in the package in the middle of the capsule shell or placed in multiple packages. It will react or dissolve in the water-absorbing wall layer under squeezing. Then react.
  • TIM TNO Intestinal Model
  • TIM-2 large intestine simulator
  • the control group is to take samples from the simulator while sampling the two types of capsules.
  • the sample is placed in a sterile Ep tube and stored in a refrigerator at -80°C for later use.
  • the drug preservation sample group and the cryopreservation sample group were taken out after staying in the simulated large intestine for 8 hours.
  • the DNA extraction kit QIAamp PowerFecal DNA Kit, Qiagen, Germany
  • the 16S rRNA gene universal primers (338F-ACTCCTACGGGAGGCAGGCAGCA, 806R-GGACTAC-HVGGGTWTCTAAT) were used for PCR amplification of the 16S rRNA gene hypervariable region V4, and the primers were respectively added with a linker sequence.
  • the DNA library is constructed, the products are sent to gene sequencing, and the sequencing results are input into Genbank for comparison.
  • the relative abundances of the drug preservation sample group, cryopreservation sample group and the control group were analyzed by one-way analysis of variance, and the results were all (P ⁇ 0.05), indicating two ways to preserve the samples, drug preservation sample, cryopreservation sample and control group
  • the difference in the structure of the intestinal flora is not significant. That is, the type and structure of the flora of the samples sampled from the drug preservation sample group, the cryopreservation sample group, and the control group are basically the same as those of the samples taken directly from the refrigerator and refrigerated.
  • test results show that the method of storing drug samples and cryopreserving samples has a good preservation effect.

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Abstract

本发明公开一种适用于动物与人的生物反应控制状态胶囊，包括胶囊壳体，胶囊壳体表面嵌入有若干单向阀门，阀门开关由压力控制；一种肠道内容物取样与冷冻保存装置，包括壳体、热电偶、压电模块和单片机。取样材料在胃肠道内的保存结构，包括取样胶囊，取样胶囊内部设置有包裹状结构，且包裹状结构内包裹有药剂。本发明有效解决了利用PH值变化触发取样，或利用电子机械胶囊取样，带来的一系列问题；提高了肠道内细菌的提取效率和质量，实现了取样材料在胃肠道内的保存取样。

Description

生物反应控制状态胶囊、肠道内容物取样与冷冻保存装置及方法、取样材料在胃肠道内的保存结构与方法 技术领域
本发明涉及医疗技术领域，特别是涉及一种生物反应控制状态胶囊、肠道内容物取样与冷冻保存装置及方法、取样材料在胃肠道内的保存结构与方法。
背景技术
人体肠道中存在大量的共生菌群，其数量超过1000万亿个，大约是人体细胞总数的10倍，同时肠道内微生物基因的数量约为300万个，大约是人类基因组基因数量的100多倍，如此海量的基因能够帮助微生物适应多变的环境，形成了与人体密不可分的共生关系。
肠道菌群与人体相互作用及影响的统一体称为肠道微生态(gut microflora)，是人体最大的微生态系统，与人类的健康和疾病密切相关，过去十年已经有大量研究及证据表明，肠道微生态可调节大脑功能，随着“脑-肠-菌群”轴学说的提出和证实，微生态的相关研究已涉及高血压、糖尿病、肠道疾病、肥胖、癌症以及中枢神经系统疾病。
要研究肠道菌群，取样装置将成为实现这一项目的理想工具，更进一步，取样装置的作用远远超过人类肠道抽样的需求和要求，不仅对肠道微生物的分布有意义，而且它们各自的副产物，他们之间的相互影响，以及肠道分泌物、毒物、肿瘤细胞、肿瘤产物等都至关重要，通过人体直接取得样本变得至关重要、必不可少。
国内外相关的研究，李会峰等人的专利：肠道内容物负压自动取样器(专利号201711255713.2)，设定胶囊内为负压，触发取样的开关是在胃、十二指肠、空回肠部位，用可以溶解的特定的膜来封口，封膜溶解后取样。美国，宝珍那提公司，流体取样装置(专利号201780051676.5)，用PH传感器，或用不同肠段可溶胶体覆盖电极，溶解后电控开关，进行取样。这些装置，依赖肠段的PH值变化或肠段对特定化合物的溶解来触发取样，这些触发点都面临分段不细、定位不准、取样不全面的问题，而且加用的 是微处理器、机械控制，一定会带来潜在的电池污染、机械损伤，还会有造价较贵、重复使用又会引发人们的心理不适等一系列问题。
另外，胃肠道内容物有食物残渣、菌群、寄生虫卵等多种成分，要分辨和获得这些成分，需要依赖一些医疗器械的辅助。正常人体肠道内的菌群已经被认为是一种特殊的器官，肠道内约有一千种细菌，多数细菌的功能以及不同细菌之间按照什么机制有机地工作，均不清楚；常用益生菌药物和食物只是肠道的一种或几种细菌；对肠道内细菌的研究已经在逐渐开展，尤其是对于常用抗生素等药物治疗无效的感染相关的疾病，其价值显得尤其重视。
已经有少数研究通过肠镜、胃镜、空肠管等进行细菌提取，但是提取过程很难在短时间内完成，就不能保证肠道内提取的细菌的质量。
由于人体肠道为微生物提供了最适宜的生长环境，一旦被取样后，微生物就脱离人体肠道环境，大多数微生物的增长与死亡速率会发生很大的改变，不能准确的反映该段胃肠道的微生物种群状况。目前通用的保存方法可以低温冻存和药剂处理，然而此类现存方法在体外可以，而针对在人或其他动物消化道内，就有很大难度。尤其是在肠道内取样后的胶囊，其内部保存的消化道内容物，要保持其活性或菌群数量不变，就是一个现实而急迫的挑战。
另外胃肠道内取样得到的材料，不仅仅包括胃肠道微生物，还有局部的蛋白、核酸、糖类、脂类等各种生物活性物，包括体内的激素等小分子物质，而这些物质在取得后，也必须得保存，方可以用来分析。美国，普罗根尼蒂公司(CN109843182A)，专利中提到很多内容物保持剂，包括使用胶类、表面活性类、抗生素类、蛋白酶类等。但是其并没考虑到具体哪一种保存剂复配效果最好，更没有考虑到在没有电子控制装备的一次性取样胶囊内，哪一种组织方式，哪一种配方会起到更好的效果。
发明内容
本发明的目的是提供一种适用于动物与人的生物反应控制状态胶囊，以解决上述现有技术存在的问题，有效解决利用PH值变化触发取样，或利用电子机械胶囊取样，带来的一系列问题；提供一种肠道内容物取样与冷冻保存装置及方法，以解决上述现有技术存在的问题，提高肠道内细菌 的提取效率和质量；还提供一种取样材料在胃肠道内的保存结构与方法，实现取样材料在胃肠道内的保存。
为实现上述目的，本发明提供了如下方案：本发明提供一种适用于动物与人的生物反应控制状态胶囊，包括胶囊壳体，所述胶囊壳体表面嵌入有若干单向阀门。
优选的，用一种、二种或二种以上的组分通过物理或化学反应或生物生长来控制压力变化。
优选的，一种组分通过胃肠道挤压后导致的性质变化进而导致压力变化，二种或多种组分分组包裹，胃肠运动挤压后包裹破裂进行反应，或参与反应的一种组分是胃肠内容物。
优选的，控制反应速度的方法，通过组分包裹多个微胶囊，每个微胶囊壁厚薄不一，或成份、结构不一，在胃肠运动的挤压下，破裂速度不一，以此控制反应速度，或通过控制不同厚度的膜的通透性，来控制肠道内容物进入胶囊的速度来控制反应速度。
优选的，所述胶囊壳体部分区域设置有特殊囊壁，所述特殊囊壁由高分子材料掺杂吸水物质制成，吸水物质可以是纤维素、蛋白质或其他可以形成毛细吸水现象的材料，囊壁的厚薄、掺杂吸水物质的量、掺杂的方式、过程，都会影响吸水速度，掺杂吸水物质囊壁的吸水速度决定了水进入囊壳内的速度，决定了水作为反应物的反应时间与速度。
优选的，胶囊壳体内部或内壁可以放置1种吸水膨胀的物质或生长膨胀的物质，或2种及2种以上遇水即可反应，反应就会导致压力变化的物质。
优选的，所述胶囊壳体内壁设置有特殊囊壁，特殊囊壁中的吸水纤维，按一定速度吸收水，胶囊壳体内部填充有二氧化碳，胶囊壁上涂覆有碱性物质与胶类物质的混合体，纤维素毛细吸水速度，决定了囊壁碱性物质与二氧化碳的反应速度，决定了气压降低的速度。
优选的，所述胶囊壳体外壁局部包围有凝胶，凝胶渗透速度决定反应速度，所述凝胶中可以含有酶分子。
优选的，所述酶分子，是指能够分解凝胶整体或部分结构的酶。
优选的，所述吸水物质、吸水膨胀的物质、胶囊壳体外壁局部包围的凝胶，主要包括天然亲水产物和人工合成的吸水聚合物，包括但不限于纤维素类、蛋白质、淀粉、琼脂糖、丙烯酸树脂类、聚乙烯醇、聚乙烯吡咯烷酮、明胶、海藻酸钠、干酪素、瓜尔胶、甲壳胺、阿拉伯树胶、黄原胶、大豆蛋白胶、天然橡胶、羊毛脂、琼脂聚丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮、聚氧化乙烯、卡波树脂、聚丙烯酸、聚丙烯酸钠、聚丙烯酸酯共聚乳液、顺丁橡胶、丁苯橡胶、聚氨酯、改性聚脲、低分子聚乙烯蜡、氨基醇络合型钛酸酯。
优选的，所述单向阀门最少为一个，且单向阀门可以是正压和负压阀门，所述弹力球为不均匀型，且弹力球设置有两个。
优选的，所述单向阀门中包括两个弹簧卡片，两个弹簧卡片通过卡块进行接触密封。
优选的，所述单向阀门内部设置四个卡块，其中两个卡块通过弹簧卡片与胶囊壳体相连，两个卡块并联安装，且通过橡皮筋与胶囊壳体相连；
所述卡块为三角形，所述胶囊壳体为弧形，且单向阀门为宽口式。
本发明还提供一种肠道内容物取样与冷冻保存装置，包括壳体、热电偶、压电模块和单片机，若干串联或并联连接的所述压电模块镶嵌在所述壳体内，所述壳体一端设有电动门组件，另一端安装热电偶，所述压电模块与单片机、电动门组件和热电偶连接，所述壳体设有用于存储样品的内腔，所述单片机通过所述电动门组件控制所述内腔的开合。
优选的，所述壳体与胶囊仿形。
优选的，所述热电偶吸热侧设置在所述壳体内，并连接有吸热网。
优选的，所述热电偶外侧安装有散热板，所述热电偶外侧与壳体侧面仿形。
优选的，所述壳体包括内壳和外壳；所述外壳由弹性材料制成，所述内壳由隔热材料制成，或所述内壳内表面设置有保温层。
优选的，所述压电模块与所述电动组件连接，所述压电模块与所述电动门组件之间连接有整流器。
优选的，所述压电模块是压电陶瓷。
优选的，所述电动门组件包括电动门和电动门开关，所述电动门开关与所述压电模块连接，所述电动门开关控制所述电动门的开闭。
本发明还提供一种肠道内容物取样与冷冻保存的方法，采用上述的肠道内容物取样与冷冻保存装置，步骤如下：压电模块受挤压产生电能提供给热电偶和电动门组件；壳体运动到设定位置取样，电动门组件关闭所述壳体的内腔，存储样品；热电偶通电对所述内腔进行制冷。
本发明还提供一种取样材料在胃肠道内的保存结构，包括取样胶囊，所述取样胶囊内部设置有包裹状结构，且包裹状结构内包裹有药剂。
优选的，所述取样胶囊内部是指胶囊的内侧壁、用支架结构推送到中央位置等(即取样胶囊内部是指胶囊的内侧壁所围成的空间)。
优选的，所述包裹状结构由吸水分解材质、半透膜材质或不透水材质组成，且药剂为三羟甲基氨基甲烷(Tris-HCl)、乙二胺四乙酸二钠(EDTA-2Na)、氯化钠(NaCl)、十二烷基硫酸钠(SDS)、卡松防腐剂、乙醇或柠檬酸钠的一种或多种的混合物。
优选的，所述包裹状结构还由易散热材料做成，且内部还包裹有硝酸铵，或其他吸水或反应能降低温度的物质。
本发明还提供一种取样材料在胃肠道内的保存方法，其方法包括以下步骤：
A、按几种不同配方，把配方中的固体成分充分混合，用吸水物质材料把其封成一个或多个小包(包裹状结构)，再用吸附、包裹等方式把它们分散在囊壳内和/或囊壳壁上；
B、囊壳设置成有一定柔软度的材料，在胃肠运动的挤压下，内容物也会被充分搅拌；
C、被取样的材料，其中水分会溶解各种吸附、包裹物质，被溶解的物质作用于取样材料，实现对取样材料的DNA的固定与保存(将取样材料和囊壳置于水中，水会溶解所述囊壳、所述包裹状结构和所述包裹状结构包裹起来的固体成分，形成水溶液，所述水溶液作用于所述取样材料，实现对所述取样材料的DNA的固定与保存)。
优选的，所述步骤A中的配方为三羟甲基氨基甲烷(Tris-HCl)缓冲液、10-50mM的乙二胺四乙酸二钠(EDTA-2Na)、100-150mM的氯化钠(NaCl)和质量分数为0.1％-0.5％的十二烷基硫酸钠(SDS)或利用乙醇、柠檬酸钠、EDTA-二钠、Tris-HCl、NaCl和十二烷基硫酸钠或常规实验用配方，且吸水物质材料以多糖类、蛋白质类为主，包括且不限于纤维素类、明胶、琼脂糖、阿拉伯胶、黄原胶、树脂类等，同时小包可以被线状材料串起来，线状材料固定在有一定间隔的囊壁上(所述线状材料上有多个固定点与所述囊壳壁固连，相邻的所述固定点之间具有间隔)，且囊壳壁用隔热材料做成，包括泡沫聚氨酯、聚苯乙烯泡沫塑料、聚苯板、酚醛泡沫橡塑海绵、聚乙烯、聚苯乙烯泡沫或玻璃棉等，同时，包裹部分用吸水材料制成，吸水材料控制反应或参与反应。
优选的，所述步骤C中的保存方式为制冷保存，且制冷保存为化学缓慢吸热反应，主要对其他生物活性物质、蛋白质、肿瘤细胞等的保存结构，用吸热的化学反应或物理变化，最好其中一种反应物是水，或者胃肠道、食物中盐类，同时，吸热反应的材料放于囊壳中间的包裹中或放于多个包裹中，挤压下会反应或吸水壁层溶解，然后反应(步骤C中的保存方式为制冷保存，且所述制冷保存采用化学缓慢吸热反应或物理吸热变化进行制冷，所述制冷保存用于保存生物活性物质、蛋白质或肿瘤细胞，所述化学缓慢吸热反应中的一种反应物是水、胃肠道的盐类或食物中的盐类，同时，所述化学缓慢吸热反应的材料放于所述包裹状结构，所述囊壳受挤压时所述所述化学缓慢吸热反应的材料会进行反应，或在所述包裹状结构溶解后进行反应)。
本发明生物反应控制状态胶囊、肠道内容物取样与冷冻保存装置及方法、取样材料在胃肠道内的保存结构与方法相对于现有技术取得了以下技术效果：
本发明适用于动物与人的生物反应控制状态胶结构科学合理，使用安全方便，通过微生物的发酵反应，生物的生长，蛋白质、纤维素等对人体无毒物质的吸水膨胀，或人体内预先设定好的与压力有关的化学反应来实现压力差，从而便于胶囊的单向阀开启，实现对于菌群的取样，并吸收储存，并且控制凝胶的反应速率，来实现不同位置的菌群提取，便于医疗研 究。本发明肠道内容物取样与冷冻保存装置及方法通过设置连通的压电模块和热电偶在壳体上，所述热电偶可以降低壳体内温度，减慢壳体内样品的反应，并把温度最终控制在有利于保存样品的温度范围。本发明取样材料在胃肠道内的保存结构与方法通过实验，得出用DNA保存药物保存的样本或者是用化学反应致冷冻方法保存的样本，在保存8个小时后，与直接取样马上冰箱冷藏8个小时的样品，其菌群种类和结构基本一致，从而证明该保存方法在体内的保存效果是稳定可靠的，可以达到冰箱的保存水平。这对于取样后材料仍然在肠道内不能及时送检，保存其菌群种类和结构的稳定性，对于取样后期的检测检查具有极其重要的意义。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1为本发明适用于动物与人的生物反应控制状态胶囊的结构示意图；
图2为本发明适用于动物与人的生物反应控制状态胶囊中囊壁、凝胶和胶囊壳体连接关系结构示意图；
图3为本发明适用于动物与人的生物反应控制状态胶囊中弹簧卡片和卡块连接关系示意图；
图4为本发明适用于动物与人的生物反应控制状态胶囊中弹簧卡片、卡块和橡皮筋连接关系结构示意图；
图5为本发明肠道内容物取样与冷冻保存装置的结构示意图；
图6为本发明肠道内容物取样与冷冻保存装置的电路原理图；
图7为本发明肠道内容物取样与冷冻保存装置中壳体取样后内腔的的温度变化曲线图；
其中，100、适用于动物与人的生物反应控制状态胶囊；1、胶囊壳体；2、单向阀门；3、囊壁；4、吸收纤维；5、二氧化碳；6、弹力球；7、弹簧卡片；8、卡块；9、橡皮筋；10、凝胶；200、肠道内容物取样与冷冻保存装置；11、弹性外壳；12、单片机；13、电动门开关；14、金属散热 壳；15、热电偶；16、金属吸热网；17、保温内壳；18、压电模块；19、壳体；sx表示未使用热电偶时壳体内的温度变化曲线；xx表示使用热电偶时壳体内的温度变化曲线。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明的目的是提供一种适用于动物与人的生物反应控制状态胶囊，以解决上述现有技术存在的问题，有效解决利用PH值变化触发取样，或利用电子机械胶囊取样，带来的一系列问题；提供一种肠道内容物取样与冷冻保存装置及方法，以解决上述现有技术存在的问题，提高肠道内细菌的提取效率和质量。
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图和具体实施方式对本发明作进一步详细的说明。
实施例1：
如图1和图2所示，本实施例提供一种适用于动物与人的生物反应控制状态胶囊100，包括胶囊壳体1，胶囊壳体1表面嵌入有若干单向阀门2，胶囊壳体1为弧形，且单向阀门2为宽口式生产中，单向阀门2最少为一个，且单向阀门2可以是正压和负压阀门，从而便于不同的环境使用，便于药物和菌群的排出与吸收；
一种组分或多种组分通过胃肠道挤压后导致的性质改变进而导致压力变化，多种组分分组包裹，胃肠运动挤压后包裹破裂进行反应，参与反应的一种组分可以是胃肠内容物，控制反应速度的方法，通过组分包裹多个胶囊，每个胶囊壁厚薄不一，从而破裂速度不一，以此控制反应速度。
可采用的方案：一组包裹内封闭碳酸盐类物质，另一组直接放入酸类物质，控制包裹厚度，根据内部包裹的微胶囊不同厚度做成系列胶囊；当取样胶囊被口服进入人体胃肠道内后，在胃肠运动的挤压作用下，一定时间后，微胶囊破裂，酸和碳酸盐起反应，产生二氧化碳，使囊内压力升高， 单向阀门被打开。随后，在胃肠运动过程中，胃肠道内的物质被挤压进入胶囊。胃肠道内物质进入胶囊后，其水分会溶解弹簧卡片固定胶，固定胶由易于吸水的胶类物质构成，像卡拉胶、黄原胶、明胶等，胶类被溶解，软化后，在弹簧作用下，胶囊口关闭，直到排出体外。
实施例2：
如图2和图3所示，本实施例提供一种适用于动物与人的生物反应控制状态胶囊100，包括胶囊壳体1，胶囊壳体1表面嵌入有若干单向阀门2，单向阀门2中包括两个弹簧卡片7，两个弹簧卡片7通过卡块8进行接触密封，且卡块8为三角形，胶囊壳体1为弧形，且单向阀门2为宽口式生产中，单向阀门2最少为一个，且单向阀门2可以是正压和负压阀门，从而便于不同的环境使用，从而便于药物的排泄和菌群的吸收；
胶囊壳体1外壁部分有凝胶10，凝胶10可选用明胶，凝胶10吸水渗透速度决定反应速度，凝胶10中含有酶分子选用蛋白酶，对凝胶物质中加相关的酶类，在胃肠道环境温度的情况下，这种凝胶状物质就可能很快液化，而且随着时间延长，液化会导致膜被溶解，相当于是阀门打开，肠道内的内容物就可以被挤压进来。内容物进入胶囊后，卡块8慢慢吸水变软，在弹簧7的作用下，慢慢关闭。
实施例3：
如图2和图3所示，本实施例提供一种适用于动物与人的生物反应控制状态胶囊100，包括胶囊壳体1，胶囊壳体1表面嵌入有若干单向阀门2，单向阀门2中包括两个弹簧卡片7，两个弹簧卡片7通过卡块8进行接触密封，且卡块8为三角形，胶囊壳体1为弧形，且单向阀门2为宽口式生产中，单向阀门2最少为一个，且单向阀门2可以是正压和负压阀门，从而便于不同的环境使用，从而便于药物的排泄和菌群的吸收；
且胶囊壳体1内壁设置有囊壁3，囊壁3中掺杂纤维素压制成，纤维素和其他不被消化有可以通过毛细现象吸水的材料制成，而成立的大小、厚度将决定吸水的速度，而吸水的速度决定了反应速度、生长速度以及压力变化的速度，优选的，内部加用了干燥的酵母菌和葡萄糖，当水分进入后，肠道环境温度的情况下，酵母菌有氧或无氧生长，产生二氧化碳，当压力达到一定程度，单向阀门2打开，肠道内的内容就可以被吸收进来， 并在单向阀门2下方的胶囊壳体1内壁连接有吸收纤维4，胶囊壳体1内部填充有二氧化碳5，且胶囊壳体1底端设置有若干弹力球6，弹力球6为不均匀型，且弹力球6设置有两个，从而便于正常的弹动。
实施例4：
如图2和图4所示，本实施例提供一种适用于动物与人的生物反应控制状态胶囊100，包括胶囊壳体1，胶囊壳体1表面嵌入有若干单向阀门2，单向阀门2内部设置四个卡块8，其中两个卡块8通过弹簧卡片7与胶囊壳体1相连，两个卡块8并联安装，且通过橡皮筋9与胶囊壳体1相连，且卡块8为三角形，胶囊壳体1为弧形，且单向阀门2为宽口式生产中，单向阀门2最少为一个，且单向阀门2可以是正压和负压阀门，从而便于不同的环境使用，从而便于药物的排泄和菌群的吸收；
二种的组分通过物理、化学反应来控制压力变化；且胶囊壳体1内壁设置有囊壁3，囊壁3中掺杂吸水材料制成，吸水材料由纤维素和其他不被消化有可以通过毛细现象吸水的材料制成，而囊壁的大小、厚度将决定吸水的速度，水进入胶囊内，优选的，胶囊内充满二氧化碳或氨气，胶囊壳体1内壁上用胶类封存有碱类物质或酸性物质，遇水，气体被迅速反应消耗掉，内部气体压力下降，当压力达到一定程度，单向阀门2打开，肠道内的内容就可以被吸收进来，并在单向阀门2下方的胶囊壳体1内壁连接有吸收纤维4，胶囊壳体1内部填充有二氧化碳5，且胶囊壳体1底端设置有若干弹力球6，弹力球6为不均匀型，且弹力球6设置有两个，从而便于正常的弹动。
实施例5：
如图2和图4所示，本实施例提供一种适用于动物与人的生物反应控制状态胶囊100，包括胶囊壳体1，胶囊壳体1表面嵌入有若干单向阀门2，单向阀门2内部设置四个卡块8，其中两个卡块8通过弹簧卡片7与胶囊壳体1相连，两个卡块8并联安装，且通过橡皮筋9与胶囊壳体1相连，且卡块8为三角形，胶囊壳体1为弧形，且单向阀门2为宽口式生产中，单向阀门2最少为一个，且单向阀门2可以是正压和负压阀门，从而便于不同的环境使用，从而便于药物的排泄和菌群的吸收；
卡块8可以由特殊囊壁3组成，也可以有透水凝胶组成，特殊囊壁3中掺杂纤维素压制成，卡块8内填充吸水物质，优选纤维素类、蛋白类、淀粉类组成，特殊囊壁或透水凝胶的大小、厚度将决定吸水的速度，而吸水的速度决定了膨胀速度，向一侧膨胀拉动弹簧卡片7或橡皮筋9，单向阀门2打开，肠道内的内容就可以被吸收进来；囊壁破裂则阀门关闭。
本发明的工作原理及使用流程：使用前，患者按照医生要求进行正常的体检与饮食，接着根据患者需要，进行采样，将胶囊壳体1吞入体内，而胶囊壳体1表面嵌入有单向阀门2，单向阀门2受到压力的时候，自动打开，通过排除二氧化碳5，将体内所需采集的菌落通过由于压力差打开的单向阀门2进入到胶囊壳体1中，而胶囊壳体1内壁连接有吸收纤维4，便于吸收采集的菌落，或者通过凝胶10进行溶解，排出胶囊壳体1中的药物，在进行采集，最后通过食物的挤压，脱离采集区，此时单向阀门2由于压力差变小，关闭单向阀门2，最后通过体内排出，实现正常的菌落采集。
实验验证：
目的：把自动取样器放入模拟的胃肠道装置中，获取阀门开关的时间和区域数据。
胶囊制作方法说明：体积大小选00、0、1号胶囊的一个，其囊壳用聚乳酸、聚丙烯腈、聚四氟乙烯等生物相容材料制成，关键的压力膨胀破裂区域选用1mm、2mm共2个数据，其囊壳厚度执行1-8mm，加纤维素织物面积0.01、0.05、0.1、0.15平方厘米，纤维素织物内部纤维布料包裹有碱性物质比如氧化钙、氧化镁粉末。内部充满二氧化碳气体。用明胶或其他胶类物质作为弹簧封口堵块，当被溶解后，开始封口。
具体步骤：把自动取样器放入模拟的胃肠道装置中，模拟的胃肠道装置选用TIM(TNO Intestinal Model)(TIM是由荷兰瓦赫宁根大学的Minekus和Havenaar研制的用于药物动态测试的多单元的计算机控制的体外消化模拟系统)。该系统分为两部分，胃、小肠模拟器(TIM-1)和大肠模拟器(TIM-2)。本实验使用TIM-1，获取阀门开关的时间和区域数据。按上述方法制作取样器，分4组，每组5个，大小0号胶囊，其囊壳用聚乳酸生物相容材料制成，关键的压力膨胀破裂区域选用1mm，使其能抵抗0.1-0.3 倍大气压即可，期囊壳厚度执行5mm，加纤维素织物面积0.01、0.05、0.1、0.15平方厘米，纤维素织物内部纤维布料包裹有碱性物质比如氧化钙+氧化镁粉末共0.1克，吸水后，开始反应，用明胶作为弹簧封口堵块，当被溶解后，开始封口。
在模拟器内，观察其封口膜破裂的时间(分钟)，与阀门开关时间(分钟)。
结果见下表：
Figure PCTCN2021080033-appb-000001
通过以上实验，证明可以在多个时间段、多个消化道区段取样，每次取样时间在20-30分钟，而据观察，在10分钟内，每个胶囊已经充满取样内容物；所以本装置基本满足胃肠道取样的要求。
实施例6：
请参阅图5和图6，本实施例还提供一种肠道内容物取样与冷冻保存装置200，包括壳体19、热电偶15、压电模块18和单片机12，若干串联或并联连接的压电模块镶嵌在壳体19内，壳体19一端设有电动门组件，另一端安装热电偶15，压电模块18与单片机12、电动门组件和热电偶15连接，壳体19设有用于存储样品的内腔，单片机12通过电动门组件控制内腔的开合。
具体的，镶嵌在壳体19内的压电模块18与单片机12、电动门组件和热电偶15电连接，压电模块18外表面设有绝缘层或绝缘膜。肠道蠕动带动壳体19运动，同时压电模块18受挤压产生电能提供给热电偶15和电动门组件；壳体19运动到设定位置，电动门组件关闭壳体19的内腔；实现肠道内样品的存取，单片机12控制热电偶15通电，热电偶15吸热侧吸收内腔的热量，热电偶15放热侧将热量放到肠道内，被吸热的内腔温度下降至设定温度，对其内的样品进行冷却保存，同时将壳体19取出。 用热电偶冷却保存样品，在被检测分析之前，很好的确保了其质量不会降低。
请参阅图5，本发明实施例中，壳体19与胶囊仿形。
具体的，壳体19的两端呈圆弧形，在肠道内运动的过程中，受到的阻力较小，还避免对肠道造成损伤。壳体19的两端呈圆弧形，中间平滑过渡。
请参阅图5，本发明实施例中，热电偶15吸热侧设置在壳体19内，并连接有吸热网。
具体的，吸热网是金属吸热网16，设有依次或多层金属吸热网16，与热电偶15吸热侧连接，将内腔的温度通过金属吸热网16及热电偶转移到壳体19外的肠道。从而实现样品的冷却保存。
本发明提供的一个优选实施例中，壳体19内预置有冷冻物质，比如干冰和氢氧化钙，以及盐的低温饱和溶液(氯化钠、硫酸钠等)，并用易导热材料(易导热材料是铜片)密封成薄片状，代替金属吸热网16，吸收内腔的热量，从而实现样品的冷却保存。
请参阅图5，本发明实施例中，热电偶15外侧安装有散热板，热电偶15外侧与壳体19侧面仿形。热电偶15的外侧与壳体19处于同一弧面。
具体的，散热板是金属散热壳14，通过金属散热壳14加快热电偶15放热侧的散热效率，使得内腔的温度不会受到肠道的影响。热电偶15外侧与壳体19侧面仿形，不会增加壳体19的阻力。
请参阅图5，本发明实施例中，壳体19包括内壳17和外壳11；外壳11由弹性材料制成，内壳17由隔热材料制成，或内壳17内表面设置有保温层。
具体的，内壳17内表面设置有保温层，由弹性材料制成的外壳11为弹性外壳，弹性材料是硅胶或热塑性弹性体(TPE)材料。
优选的，弹性材料是TPE弹性体材料，相比与硅胶，TPE弹性体材料的软硬度和弹性与硅胶相当，但TPE弹性体材料可快速的注塑或挤压成型，还可百分百回收利用。内壳17由隔热材料制成，制成保温内壳，隔热材料可以是聚苯乙烯泡沫塑料、聚氨酯泡沫塑料或酚醛泡沫材料的任 意一种或多种组合。隔热材料包括但不限于上述的聚苯乙烯泡沫塑料、聚氨酯泡沫塑料或酚醛泡沫材料。
请参阅图6，压电模块18与电动门组件连接，压电模块与电动门组件之间连接有整流器。
具体的，整流器将压电模块18的交流电转换为直流电供给给电动门组件和热电偶15。电动门组件包括电动门开关13和电动门，电动门开关13与单片机连接，单片机12上集成有时钟电路，时钟电路控制电动门开关13通电，电动门开关13通电后控制电动门关闭。
时钟电路可以采用DS1302或DS1307，DS1302是一种具有涓细电流充电能力的电路，主要特点是采用串行数据传输，可为掉电保护电源提供可编程的充电功能，并且可以关闭充电功能。
请参阅图5，本发明实施例中，压电模块18是压电陶瓷。
具体的，压电陶瓷8可以是钛酸钡系、锆钛酸铅二元系或三元系或多元系压电陶瓷；优选多元系压电陶瓷，压电陶瓷由石英晶体、钛酸钡、鋯钛酸铅、聚双氟亚乙烯、氧化锂铌、氧化锌、硫化镉亚乙烯基二氰、乙酸乙烯酯、异丁烯、甲基丙烯酸甲酯、苯甲酸乙烯酯进行共聚反应生成。压电陶瓷8与热电偶及电动门组件连接，为热电偶和电动门组件提供电能。
本实施例还提供一种肠道内容物取样与冷冻保存的方法，采用上述的肠道内容物取样与冷冻保存装置200，步骤如下：肠道蠕动带动壳体19运动，压电模块受挤压产生电能提供给热电偶和电动门组件；壳体19运动到设定位置取样，电动门组件关闭壳体19的内腔，存储样品；热电偶通电对内腔进行制冷，将壳体19取出。
具体的，肠道蠕动带动壳体19运动，同时压电模块18受挤压产生电能提供给热电偶15和电动门组件；壳体19运动到设定位置，电动门组件关闭壳体19的内腔；实现肠道内样品的存取，单片机12控制热电偶15通电，热电偶15吸热侧吸收内腔的热量，热电偶15放热侧将热量放到肠道内，被吸热的内腔温度下降至设定温度，对其内的样品进行冷却保存。
如图7，本发明的一个实施例中，sx表示未使用热电偶时壳体19内的温度变化曲线；xx表示使用热电偶时壳体19内的温度变化曲线。采用两组壳体19进行对比实验，分别是不带热电偶壳体19、带热电偶壳体19， 把不带热电偶壳体19、带热电偶壳体19分别放入模拟的胃肠道装置中，模拟的胃肠道装置选用大肠模拟器。分为1、2组分别对应药物保存样本组与对照组二部分的取样，每组五个壳体19；环境温度25度，两类壳体19取样内部放入温度传感器探头，在不影响操作时，记录壳体19内温度数据，设定壳体19取样时间点在开始4小时，实验时间共12小时。对照组不连热电偶，其他条件一样。实验结果如图7中sx、xx显示，热电偶可以降低壳体19内温度，可以减慢壳体19内的反应，并把温度最终控制在1-5摄氏度之间，有利的对样品进行了保存。
本发明的工作原理：肠道蠕动带动壳体19运动，同时压电模块18受挤压产生电能提供给热电偶15和电动门组件；壳体19运动到设定位置，电动门组件关闭壳体19的内腔；实现肠道内样品的存取，单片机12控制热电偶15通电，热电偶15吸热侧吸收内腔的热量，热电偶15放热侧将热量放到肠道内，被吸热的内腔温度下降至设定温度，对其内的样品进行冷却保存。
实施例7：
本实施例提供一种取样材料在胃肠道内的保存结构，包括取样胶囊，取样胶囊内部设置有包裹状结构，且包裹状结构内包裹有药剂，取样胶囊内部是指胶囊的内侧壁、用支架结构推送到中央位置等，包裹状结构由吸水分解材质、半透膜材质或不透水材质组成，且药剂为三羟甲基氨基甲烷(Tris-HCl)、乙二胺四乙酸二钠(EDTA-2Na)、氯化钠(NaCl)、十二烷基硫酸钠(SDS)、卡松防腐剂、乙醇或柠檬酸钠的一种或多种的混合物，包裹状结构还由易散热材料做成，且内部还包裹有硝酸铵，或其他吸水或反应能降低温度的物质。
本实施例还提供一种取样材料在胃肠道内的保存方法，其方法包括以下步骤：
A、按几种不同配方，把配方中的固体成分充分混合，用吸水物质材料把其封成一个或多个小包，再用吸附、包裹等方式把它们分散在囊壳内和/或囊壳壁上；
B、囊壳设置成有一定柔软度的材料，在胃肠运动的挤压下，内容物也会被充分搅拌；
C、被取样的材料，其中水分会溶解各种吸附、包裹物质，被溶解的物质作用于取样材料，实现对取样材料的DNA的固定与保存。
步骤A中的配方为三羟甲基氨基甲烷(Tris-HCl)缓冲液、10-50mM的乙二胺四乙酸二钠(EDTA-2Na)、100-150mM的氯化钠(NaCl)和质量分数为0.1％-0.5％的十二烷基硫酸钠(SDS)或利用乙醇、柠檬酸钠、EDTA-二钠、Tris-HCl、NaCl和十二烷基硫酸钠或常规实验用配方，且吸水物质材料以多糖类、蛋白质类为主，包括且不限于纤维素类、明胶、琼脂糖、阿拉伯胶、黄原胶、树脂类等，同时，小包可以被线状材料串起来，线状材料固定在有一定间隔的囊壁上，且囊壳壁用隔热材料做成，包括泡沫聚氨酯、聚苯乙烯泡沫塑料、聚苯板、酚醛泡沫橡塑海绵、聚乙烯、聚苯乙烯泡沫或玻璃棉等，同时，包裹部分用吸水材料制成，吸水材料控制反应或参与反应。
步骤C中的保存方式为制冷保存，且制冷保存为化学缓慢吸热反应，主要对其他生物活性物质、蛋白质、肿瘤细胞等的保存结构，用吸热的化学反应或物理变化，最好其中一种反应物是水，或者胃肠道、食物中盐类，同时，吸热反应的材料放于囊壳中间的包裹中或放于多个包裹中，挤压下会反应或吸水壁层溶解，然后反应。
实验验证及具体步骤：把取样胶囊放入模拟的胃肠道装置中，模拟的胃肠道装置选用TIM(TNO Intestinal Model)(TIM是由荷兰瓦赫宁根大学的Minekus和Havenaar研制的用于药物动态测试的多单元的计算机控制的体外消化模拟系统)。该系统分为两部分，胃、小肠模拟器(TIM-1)和大肠模拟器(TIM-2)。本实验采用肠道菌群最复杂的大肠模拟器(TIM-2)作为检测装置。
分为1、2、3组分别对应药物保存样本组、冷冻保存样本组与对照组三部分的取样，每组五个胶囊；对照组为在两类胶囊取样的同时，从模拟器中取样并样本放于无菌Ep管中，储存于-80℃冰箱中冻存备用。药物保存样本组、冷冻保存样本组分别在模拟大肠中停留8个小时后取出。最终我们对三组样品，使用DNA提取试剂盒(QIAamp PowerFecal DNA Kit，德国Qiagen公司)进行总DNA提取。用细菌的16SrRNA基因的通用引物(338F－ACTCCTACGGGAGGCAGGCAGCA，806R－GGACTAC－ HVGGGTWTCTAAT)对16SrRNA基因高度可变区V4进行PCR扩增，引物分别加上一段接头序列。构建DNA文库，产物送基因测序，测序结果输入Genbank进行比对。
肠道微生物分布情况，大肠部分菌群丰富度平均值对比指标结果见下表：
Figure PCTCN2021080033-appb-000002
药物保存样本组、冷冻保存样本组分别与对照组的相对丰度经单因素方差分析，结果均为(P<0.05)，表明两种保存样品的方法，药物保存样本、冷冻保存样本与对照组在肠道菌群种类结构之间的差异不显著。即药物保存样本组、冷冻保存样本组与对照组取样的样品的菌群种类和结构与直接取样、冰箱冷藏的样品的菌群种类和结构基本一致。
综上试验结果表明，药物保存样本与冷冻保存样本的方法具有很好的保存效果。
本发明中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想；同时，对于本领域的一般技术人员，依据本发明的思想，在具体实施方式及应用范围上均会有改变之处。综上所述，本说明书内容不应理解为对本发明的限制。

Claims (33)

  1. 一种适用于动物与人的生物反应控制状态胶囊，其特征在于：包括胶囊壳体，所述胶囊壳体表面嵌入有若干单向阀门，阀门开关由压力控制。
  2. 根据权利要求1所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于：用一种、二种或二种以上的组分通过物理或化学反应或生物生长来控制压力变化。
  3. 根据权利要求2所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于：一种组分通过胃肠道挤压后导致的性质变化进而导致压力变化，二种或多种组分分组包裹，胃肠运动挤压后包裹破裂进行反应，或参与反应的一种组分是胃肠内容物。
  4. 根据权利要求3所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于：控制反应速度的方法，通过组分被包裹成多个微胶囊，每个微胶囊壁厚薄不一，或成份、结构不一，从而破裂速度不一，以此控制反应速度，或通过控制膜的通透性，来控制肠道内容物进入胶囊的速度来控制反应速度。
  5. 根据权利要求1所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于，所述胶囊壳体部分区域设置有特殊囊壁，所述特殊囊壁由高分子材料掺杂吸水物质制成，掺杂吸水物质囊壁的吸水速度决定了水进入囊壳内的速度，决定了水作为反应物的反应时间与速度。
  6. 根据权利要求1所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于，所述单向阀门最少为一个，且单向阀门为正压和负压阀门，所述弹力球为不均匀型，且弹力球设置有两个。
  7. 根据权利要求5所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于，胶囊壳体内部或内壁放置1种吸水膨胀的物质或生长膨胀的物质，或2种及2种以上遇水即可反应，反应就会导致压力变化的物质。
  8. 根据权利要求1所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于，所述胶囊壳体外壁局部包围有凝胶，凝胶渗透速度决定反应速度，所述凝胶中含有酶分子。
  9. 根据权利要求1所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于，所述单向阀门中包括两个弹簧卡片，两个弹簧卡片通过卡块进行接触密封。
  10. 根据权利要求1所述的一种适用于动物与人的生物反应控制状态胶囊，其特征在于，所述单向阀门内部设置四个卡块，其中两个卡块通过弹簧卡片与胶囊壳体相连，两个卡块并联安装，且通过橡皮筋与胶囊壳体相连；
    所述卡块由部分特殊囊壁或凝胶包裹吸水材料制成。
  11. 一种肠道内容物取样与冷冻保存装置，其特征在于，包括壳体、热电偶、压电模块和单片机，若干串联或并联连接的所述压电模块镶嵌在所述壳体内，所述壳体一端设有电动门组件，另一端安装热电偶，所述压电模块与单片机、电动门组件和热电偶连接，所述壳体设有用于存储样品的内腔，所述单片机通过所述电动门组件控制所述内腔的开合。
  12. 根据权利要求11所述的一种肠道内容物取样与冷冻保存装置，其特征在于，所述壳体与胶囊仿形。
  13. 根据权利要求11所述的一种肠道内容物取样与冷冻保存装置，其特征在于，所述热电偶吸热侧设置在所述壳体内，并连接有吸热网，吸热网内部做成空心结构，以填充预冷物质。
  14. 根据权利要求11-13任意一项所述的一种肠道内容物取样与冷冻保存装置，其特征在于，所述热电偶外侧安装有散热板。
  15. 根据权利要求14所述的一种肠道内容物取样与冷冻保存装置，其特征在于，所述壳体包括内壳和外壳；所述外壳由弹性材料制成，所述内壳由隔热材料制成，或所述内壳内表面设置有保温层。
  16. 根据权利要求11所述的一种肠道内容物取样与冷冻保存装置，其特征在于，所述压电模块与所述电动门组件之间连接有整流器。
  17. 根据权利要求11或16所述的一种肠道内容物取样与冷冻保存装置，其特征在于，所述压电模块是压电陶瓷。
  18. 根据权利要求11所述的一种肠道内容物取样与冷冻保存装置，其 特征在于，所述电动门组件包括电动门和电动门开关，所述电动门开关与所述压电模块连接，所述电动门开关控制所述电动门的开闭。
  19. 一种肠道内容物取样与冷冻保存的方法，其特征在于，采用如权利要求11-18任意一项所述的肠道内容物取样与冷冻保存装置，步骤如下：
    压电模块受挤压产生电能提供给热电偶和电动门组件；
    壳体运动到设定位置取样，电动门组件关闭所述壳体的内腔，存储样品；
    热电偶通电对所述内腔进行制冷。
  20. 取样材料在胃肠道内的保存结构，包括取样胶囊，其特征在于：所述取样胶囊内部设置有包裹状结构，且包裹状结构内包裹有药剂。
  21. 根据权利要求20所述的取样材料在胃肠道内的保存结构，其特征在于：所述取样胶囊内部是指胶囊的内侧壁、用支架结构推送到中央位置等。
  22. 根据权利要求20所述的取样材料在胃肠道内的保存结构，其特征在于：所述包裹状结构由吸水分解材质、半透膜材质或不透水材质组成，且药剂为三羟甲基氨基甲烷(Tris-HCl)、乙二胺四乙酸二钠(EDTA-2Na)、氯化钠(NaCl)、十二烷基硫酸钠(SDS)、卡松防腐剂、乙醇或柠檬酸钠的一种或多种的混合物。
  23. 根据权利要求20所述的取样材料在胃肠道内的保存结构，其特征在于：所述包裹状结构还由易散热材料做成，且内部还包裹有硝酸铵，或其他吸水或反应能降低温度的物质。
  24. 取样材料在胃肠道内的保存方法，其特征在于：其方法包括以下步骤：
    A、按几种不同配方，把配方中的固体成分充分混合，用吸水物质材料把其封成一个或多个小包，再用吸附、包裹等方式把它们分散在囊壳内和/或囊壳壁上；
    B、囊壳设置成有一定柔软度的材料，在胃肠运动的挤压下，内容物 也会被充分搅拌；
    C、被取样的材料，其中水分会溶解各种吸附、包裹物质，被溶解的物质作用于取样材料，实现对取样材料的DNA的固定与保存。
  25. 根据权利要求24所述的取样材料在胃肠道内的保存方法，其特征在于：所述步骤A中的配方为三羟甲基氨基甲烷(Tris-HCl)缓冲液、10-50mM的乙二胺四乙酸二钠(EDTA-2Na)、100-150mM的氯化钠(NaCl)和质量分数为0.1％-0.5％的十二烷基硫酸钠(SDS)或利用乙醇、柠檬酸钠、EDTA-二钠、Tris-HCl、NaCl和十二烷基硫酸钠或常规实验用DNA保存配方，且吸水物质材料以多糖类、蛋白质类为主，包括且不限于纤维素类、明胶、琼脂糖、阿拉伯胶、黄原胶、树脂类等，同时，小包可以被线状材料串起来，线状材料固定在有一定间隔的囊壁上，且囊壳壁用隔热材料做成，包括泡沫聚氨酯、聚苯乙烯泡沫塑料、聚苯板、酚醛泡沫橡塑海绵、聚乙烯、聚苯乙烯泡沫或玻璃棉等，同时，包裹部分用吸水材料制成，吸水材料控制反应或参与反应。
  26. 根据权利要求24所述的取样材料在胃肠道内的保存方法，其特征在于：所述步骤C中的保存方式为制冷保存，且制冷保存为化学缓慢吸热反应，主要对其他生物活性物质、蛋白质、肿瘤细胞等的保存结构，用吸热的化学反应或物理变化，最好其中一种反应物是水，或者胃肠道、食物中盐类，同时，吸热反应的材料放于囊壳中间的包裹中或放于多个包裹中，挤压下会反应或吸水壁层溶解，然后反应。
  27. 取样材料在胃肠道内的保存结构，包括取样胶囊，其特征在于：所述取样胶囊内部设置有包裹状结构，且所述包裹状结构内包裹有药剂。
  28. 根据权利要求27所述的取样材料在胃肠道内的保存结构，其特征在于：所述取样胶囊内部是指胶囊的内侧壁所包裹的空间。
  29. 根据权利要求27所述的取样材料在胃肠道内的保存结构，其特征在于：所述包裹状结构由吸水分解材质、半透膜材质或不透水材质组成，且所述药剂为三羟甲基氨基甲烷(Tris-HCl)、乙二胺四乙酸二钠(EDTA-2Na)、氯化钠(NaCl)、十二烷基硫酸钠(SDS)、卡松防腐剂、乙醇或柠檬酸钠中的一种或多种的混合物。
  30. 根据权利要求27所述的取样材料在胃肠道内的保存结构，其特征在于：所述包裹状结构由易散热材料制成，且所述包裹状结构内部还包裹有硝酸铵，或其他吸水或反应能降低温度的物质。
  31. 取样材料在胃肠道内的保存方法，其特征在于：其方法包括以下步骤：
    A、按几种不同配方，把配方中的固体成分充分混合，用吸水物质材料把其封成一个或多个包裹状结构，再用吸附、包裹的方式将全部所述包裹状结构分散在囊壳内和/或囊壳壁上；
    B、囊壳采用柔性材料，在胃肠运动的挤压下，所述囊壳的内容物会被充分搅拌；
    C、将取样材料和囊壳置于水中，水会溶解所述囊壳、所述包裹状结构和所述包裹状结构包裹起来的固体成分，形成水溶液，所述水溶液作用于所述取样材料，实现对所述取样材料的DNA的固定与保存。
  32. 根据权利要求31所述的取样材料在胃肠道内的保存方法，其特征在于：所述步骤A中的配方为三羟甲基氨基甲烷(Tris-HCl)缓冲液、10-50mM的乙二胺四乙酸二钠(EDTA-2Na)、100-150mM的氯化钠(NaCl)和质量分数为0.1％-0.5％的十二烷基硫酸钠(SDS)或利用乙醇、柠檬酸钠、EDTA-二钠、Tris-HCl、NaCl和十二烷基硫酸钠或常规实验用DNA保存配方，且吸水物质材料以多糖类、蛋白质类为主，包括且不限于纤维素类、明胶、琼脂糖、阿拉伯胶、黄原胶、树脂类，同时，所述包裹状结构能够被线状材料串起来，所述线状材料上有多个固定点与所述囊壳壁固连，相邻的所述固定点之间具有间隔，且所述囊壳壁用隔热材料做成，所述隔热材料为泡沫聚氨酯、聚苯乙烯泡沫塑料、聚苯板、酚醛泡沫橡塑海绵、聚乙烯、聚苯乙烯泡沫或玻璃棉，同时，所述包裹状结构用吸水材料制成，吸水材料控制反应或参与反应。
  33. 根据权利要求31所述的取样材料在胃肠道内的保存方法，其特征在于：步骤C中的保存方式为制冷保存，且所述制冷保存采用化学缓慢吸热反应或物理吸热变化进行制冷，所述制冷保存用于保存生物活性物质、蛋白质或肿瘤细胞，所述化学缓慢吸热反应中的一种反应物是水、胃 肠道的盐类或食物中的盐类，同时，所述化学缓慢吸热反应的材料放于所述包裹状结构，所述囊壳受挤压时所述所述化学缓慢吸热反应的材料会进行反应，或在所述包裹状结构溶解后进行反应。
PCT/CN2021/080033 2020-03-11 2021-03-10 生物反应控制状态胶囊、肠道内容物取样与冷冻保存装置及方法、取样材料在胃肠道内的保存结构与方法 WO2021180133A1 (zh)

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