WO2016117599A1 - Bioréacteur doté d'un dispositif pour fournir des micro/nano-bulles contenant de l'oxygène et des micro/nano-bulles contenant un gaz microbicide tel que l'ozone - Google Patents

Bioréacteur doté d'un dispositif pour fournir des micro/nano-bulles contenant de l'oxygène et des micro/nano-bulles contenant un gaz microbicide tel que l'ozone Download PDF

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WO2016117599A1
WO2016117599A1 PCT/JP2016/051567 JP2016051567W WO2016117599A1 WO 2016117599 A1 WO2016117599 A1 WO 2016117599A1 JP 2016051567 W JP2016051567 W JP 2016051567W WO 2016117599 A1 WO2016117599 A1 WO 2016117599A1
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micro
biological reaction
culture
microorganisms
ozone
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PCT/JP2016/051567
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English (en)
Japanese (ja)
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信秀 国友
宏記 藤井
伸宏 田中
和矩 熊田
正守 樋口
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三菱化学エンジニアリング株式会社
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Priority to JP2016570680A priority Critical patent/JP6850609B2/ja
Publication of WO2016117599A1 publication Critical patent/WO2016117599A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
    • B01D65/02—Membrane cleaning or sterilisation ; Membrane regeneration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
    • B01D65/02—Membrane cleaning or sterilisation ; Membrane regeneration
    • B01D65/06—Membrane cleaning or sterilisation ; Membrane regeneration with special washing compositions
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/04—Apparatus for enzymology or microbiology with gas introduction means
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor

Definitions

  • the present invention relates to a biological reaction apparatus for culturing microorganisms or cells (hereinafter referred to as “microorganisms”) and a biological reaction method using the biological reaction apparatus, and a culture solution containing microorganisms, cells, or a medium after completion of the biological reaction.
  • the cleaning liquid contains micro-nano bubbles containing a gas having a sterilizing property such as ozone, so that sterilization / sterilization of microorganisms and the like is efficiently, economically and sufficiently performed.
  • a biological reaction is carried out in which microorganisms and the like are cultured in a culture tank to produce chemicals such as organic acids and alcohols and useful chemical substances such as antibodies.
  • Biological reactions differ from chemical reactions in that the reaction itself is slow, but because it does not use much energy and many chemical substances, it is a mild and meaningful reaction for the environment.
  • the biological reaction generally has a problem that the reaction is mild and slow. That is, for chemical reactions, a reaction within one hour is often sufficient, whereas in the case of biological reactions, a reaction time of several days or longer, several days or particularly several weeks or longer is required. There is also. For this reason, it is required to perform biological reactions efficiently and economically.
  • Patent Document 1 discloses that cell growth is promoted by culturing cells in a culture solution containing microbubbles.
  • Patent Documents 2 to 5 in the culture of microorganisms, the presence of micro-nano bubbles or nano bubbles in the culture solution promotes the activation of microorganisms, improves the reaction efficiency of biological reactions, shortens the reaction time, etc. Is disclosed.
  • Patent Document 1 describes that a microbubble is contained in the filtrate taken out of the culture solution in the culture vessel and supplied to the culture vessel.
  • Patent Document 2 describes that in a batch system, a culture solution is extracted from a culture tank, filtered through a bacterial cell filter to obtain a filtrate, and micronano bubbles are mixed with the filtrate and returned to the culture tank. ing.
  • Patent Document 3 describes mixing micro-nano bubbles and nano bubbles in the culture solution before supplying the culture solution to the culture vessel.
  • Patent Document 4 supplies the culture solution to the culture vessel. It is described that the micro / nano bubbles are mixed in the previous stage.
  • the sterilization / sterilization method using water vapor requires facilities and labor for sterilization / sterilization, and the sterilization / sterilization method using chemicals makes it difficult to ensure the safety of workers. Further, a waste water treatment means for neutralizing or decomposing the drug remaining after sterilization is required, and there is a possibility that damage such as corrosion may occur in the biological reaction apparatus.
  • a waste water treatment means for neutralizing or decomposing the drug remaining after sterilization is required, and there is a possibility that damage such as corrosion may occur in the biological reaction apparatus.
  • filtration membranes 1) having a complicated shape; 2) When the filtration membrane is dried, the filtration function is reduced. 3) Since the filtration membrane is inferior in heat resistance as compared with the culture tank and peripheral equipment, it is difficult to sterilize the details sufficiently without deteriorating the function of the filtration membrane.
  • JP 2011-120535 A Japanese Patent No. 4146476 Japanese Patent No. 4805120 Japanese Patent No. 4956552 JP 61-242605 A Japanese Patent Publication No. 08-004726 JP 2013-226486 A
  • the problem of the biological reaction device of the present invention and the biological reaction method using this biological reaction device is that sterilization and sterilization of microorganisms used in the biological reaction can be efficiently, economically and sufficiently performed after the biological reaction is completed.
  • a biological reaction apparatus and a biological reaction method using this biological reaction apparatus more specifically, 1) At the time of biological reaction, biological reaction using microorganisms can be performed efficiently and economically. At the time of cleaning / sterilization after the completion of biological reaction, cleaning / sterilization of biological reaction devices, especially filter membranes, etc.
  • An object of the present invention is to provide a biological reaction apparatus capable of efficiently, economically and sufficiently performing sterilization and sterilization of microorganisms and the like and a biological reaction method using this biological reaction apparatus.
  • microbes or microbubbles containing sterilizing gas such as ozone. And sterilizing and sterilizing using “micro-nano bubbles such as ozone”).
  • the biological reaction device of the present invention and the biological reaction method using the biological reaction device are configured to remove microorganisms and the like during the biological reaction by the micro / nano bubble generation device provided in the biological reaction device.
  • the contained culture solution contains oxygen-containing micro / nano bubbles (hereinafter referred to as “oxygen micro / nano bubbles”), and the cleaning solution contains micro / nano bubbles such as ozone during cleaning and sterilization after the completion of the biological reaction.
  • oxygen micro / nano bubbles oxygen-containing micro / nano bubbles
  • the cleaning solution contains micro / nano bubbles such as ozone during cleaning and sterilization after the completion of the biological reaction.
  • a concentrated liquid such as microorganisms contained in an inactivation tank is made to contain micro-nano bubbles such as ozone.
  • micro nano bubble of the present invention means “micro bubble” and / or “nano bubble”. “Normal bubbles” rapidly rise in the liquid and burst and disappear on the surface, whereas microbubbles with a diameter of 50 ⁇ m or less called “microbubbles” shrink in the liquid and disappear. At the same time, “nanobubbles” which are ultrafine bubbles having a diameter of 100 nm or less are generated together with free radicals, and these “nanobubbles” remain in the liquid for a certain long time.
  • Nano bubbles which are very small bubbles, are also called “ultra fine bubbles”.
  • ISO International Organization for Standardization
  • the creation of an international standard for fine bubble technology is being considered, and once the international standard is created, the name of “nanobubble”, which is currently commonly used, There is a possibility that it will be unified into “Ultra Fine Bubble”.
  • ozone As the “gas having bactericidal properties such as ozone” contained in the micro-nano bubbles such as ozone of the present invention, ozone, carbon dioxide (CO 2 ), chlorine dioxide (ClO 2 ), or a mixture thereof can be used. However, it is preferable to use ozone alone from the viewpoints of sterilization and handling.
  • ozone is self-degradable, the advantage of simplifying wastewater treatment facilities when sterilizing and sterilizing microorganisms, etc. using micro-nano bubbles containing ozone, compared to using chemicals There is also.
  • the present invention uses micro / nano bubbles such as ozone that remain sterilized and sterilized immediately after completion of a biological reaction, rapidly lysing and diffusing in a liquid such as a washing liquid and a culture liquid containing microorganisms. Can be done efficiently, economically and satisfactorily. That is, the method using water vapor requires equipment and labor, and the method using chemicals makes it difficult to sufficiently ensure the safety of workers, and neutralizes or decomposes the chemicals remaining after sterilization.
  • the sterilization / sterilization method using micro-nano bubbles such as ozone according to the present invention, there is a possibility that a waste water treatment means is separately required and the biological reaction apparatus may be damaged.
  • Micro-nano bubbles quickly dissolve and spread in liquids such as washing liquids and culture liquids containing microorganisms and remain for a long time, so that sterilization and sterilization of microorganisms can be performed efficiently, economically and sufficiently.
  • sterilization with a gas having sterilizing properties such as ozone, even in places where the liquid such as the culture liquid containing the washing liquid or microorganisms such as the upper part of the culture tank or inactivation tank is not in direct contact. Kill It is possible to exert an effect.
  • the present invention makes it possible to efficiently carry out a biological reaction using microorganisms or the like by containing micro-nano bubbles of oxygen that rapidly dissolve and diffuse in the liquid and remain for a long time in a culture solution containing microorganisms or the like during a biological reaction. It can be performed economically, economically and sufficiently, and at the time of cleaning and sterilization after the end of the biological reaction, by adding micro-nano bubbles such as ozone that quickly dissolves and diffuses in the liquid and remains for a long time in the cleaning liquid, Biological reactors, particularly filtration membranes, can be economically and sufficiently cleaned and sterilized. Further, as described above, sterilization and sterilization action can be exerted by a gas having a sterilizing property such as ozone even on a portion where the cleaning liquid is not in direct contact with the upper part of the culture tank.
  • the present invention quickly dissolves and diffuses in a concentrated liquid such as microorganisms contained in an inactivation tank when the culture liquid used for the biological reaction is discharged from the biological reaction apparatus after the biological reaction is completed.
  • a concentrated liquid such as microorganisms contained in an inactivation tank
  • micro-nano bubbles such as ozone that remain for a long time
  • microorganisms and the like can be sterilized efficiently, economically and sufficiently and discharged out of the biological reaction apparatus.
  • sterilization and sterilization action can be exerted by a gas having sterilizing properties such as ozone even on a place where a culture solution containing microorganisms or the like is not in direct contact, such as the upper part of the inactivation tank. .
  • the biological reaction of the present invention is to cause a microorganism or the like to produce a reaction product using a culture solution as a nutrient source in a culture solution containing microorganisms or the like housed in a culture tank.
  • the “culture tank” in the present invention means “one culture tank” in the above type 1), and “incubation tank” and “another tank such as a fermenter” in the above type 2). Means.
  • saccharides As the culture medium (nutrient source for microorganisms and the like) in the present invention, saccharides, nitrogen-containing compounds and the like are used.
  • saccharides saccharides such as maltose, sucrose, glucose, fructose, and mixtures thereof are usually used.
  • concentration of saccharides in the culture solution is not particularly limited, but is set to 0.1 to 10 w / v%. preferable.
  • nitrogen-containing compound ammonium chloride, ammonium sulfate, corn steep liquor, yeast extract, meat extract, peptone or the like is used, and it is preferably set to 0.1 to 10 w / v%.
  • vitamins, inorganic salts, and the like to the culture solution as needed, in addition to sugars and nitrogen-containing compounds.
  • Examples of the cell in the present invention include an animal cell for producing a physiologically active peptide or protein used as an antibody drug, particularly a genetically modified animal cell.
  • microorganisms in addition to aspergillus such as Aspergillus, aerobic or facultative anaerobic microorganisms such as Bacillus natto, acetic acid bacteria, yeast, and lactic acid bacteria conventionally used in the technical fields such as brewing and fermentation, genes Various aerobic microorganisms created by recombinant technology can be used.
  • the reaction product produced in the culture tank is extracted from the culture tank together with a culture solution containing microorganisms and the like, separated into microorganisms and filtrate with a filter, and the reaction product is recovered from the filtrate.
  • the filter of the present invention comprises a filtration membrane and a container that accommodates the filtration membrane.
  • the filtration membrane may be an organic membrane or an inorganic membrane.
  • As the shape of the filtration membrane any shape such as a flat membrane, a hollow fiber membrane, and a spiral type can be adopted. Among these, a hollow fiber membrane module is preferable, and any one of an external pressure type and an internal pressure type can be adopted as long as it is a hollow fiber membrane module.
  • a culture solution containing reaction products, microorganisms and the like is filtered while being supplied to the inside of the hollow fiber membrane, and the filtrate is taken out from the outside through the hollow fiber membrane. Since membrane dirt such as accumulated microorganisms is scraped off by the shearing force generated by the parallel flow of the culture solution, a stable filtration state can be maintained over a long period of time.
  • steady operation is performed at a circulation flow rate of about 1 to 2 m / s when using an organic membrane and about 1 to 3 m / s when using a ceramic membrane.
  • a circulation flow rate of about 1 to 2 m / s when using an organic membrane and about 1 to 3 m / s when using a ceramic membrane.
  • the circulation rate can be reduced to about 0.2 to 1.5 m / s.
  • the flux can be increased by about 1.2 to 2.0 times.
  • an organic polymer compound can be suitably used from the viewpoints of separation performance, water permeability, and dirt resistance.
  • examples include polyethylene resins, polypropylene resins, polyvinyl chloride resins, polyvinylidene fluoride resins, polysulfone resins, polyethersulfone resins, polyacrylonitrile resins, cellulose resins, and cellulose triacetate resins. A mixture of these resins as the main component may be used.
  • a vinylidene chloride resin or a resin containing the vinylidene fluoride resin as a main component is more preferably used because it has a characteristic of having both chemical strength (particularly chemical resistance) and physical strength.
  • the polyvinylidene fluoride-based resin a homopolymer of vinylidene fluoride is preferably used.
  • the polyvinylidene fluoride resin may be a copolymer of a vinyl monomer copolymerizable with vinylidene fluoride.
  • vinyl monomers copolymerizable with vinylidene fluoride include tetrafluoroethylene, hexafluoropropylene, and ethylene trichloride fluoride.
  • the average pore diameter of the filtration membrane can be appropriately determined according to the purpose and situation of use, but it is preferably smaller to some extent, and is usually preferably 0.01 ⁇ m or more and 1 ⁇ m or less.
  • the average pore diameter of the hollow fiber membrane is less than 0.01 ⁇ m, components such as microorganisms, such as sugars and proteins, and membrane dirt components such as aggregates thereof block the pores, and stable operation cannot be performed.
  • it is preferably 0.02 ⁇ m or more, and more preferably 0.03 ⁇ m or more.
  • the average pore diameter approaches the size of a microorganism or the like, these may directly block the pores.
  • the average pore diameter is 0.4 ⁇ m. The following is preferable, and 0.2 ⁇ m or less is preferable.
  • the average pore diameter of the filtration membrane can be obtained by measuring and averaging the diameters of a plurality of pores observed by scanning electron microscope observation at a magnification of 10,000 times or more.
  • 10 or more, preferably 20 or more pores are randomly selected, the diameters of these pores are measured, and the number average is obtained.
  • an image processing device or the like it is also preferable to use an image processing device or the like to obtain a circle having an area equal to the area of the pores, that is, an equivalent circle, and obtain the equivalent circle diameter as the pore diameter. it can.
  • the recovery of the target product may be performed batchwise or continuously.
  • the culture tank pump is driven to transfer the filtered filtrate to the filtrate storage tank.
  • the filtered filtrate is balanced with the amount of the culture solution supplied to the culture vessel so that the water level of the culture solution containing microorganisms in the culture vessel is kept constant. Extract and transfer to the filtrate storage tank.
  • the batch type or the continuous type can be selected as appropriate in consideration of the efficiency of biological reaction, the required purity of the target product, economy, and the like.
  • the first feature of the present invention is that, as described above, after the completion of the biological reaction, sterilization / sterilization of microorganisms, etc. is performed by using micro / nano bubbles such as ozone that rapidly dissolves and diffuses in the liquid and remains for a long time. To do efficiently, economically and adequately.
  • the conventional method using water vapor requires equipment and labor, and the conventional method using chemicals makes it difficult to sufficiently ensure the safety of the worker.
  • the waste water treatment means for neutralizing or decomposing the remaining chemicals is required separately, and there is a risk of damage such as corrosion in the bioreactor, whereas the micro-nano bubbles such as ozone of the present invention are used.
  • micro-nano bubbles such as ozone are quickly dissolved and diffused in the culture solution or washing solution and remain for a long time, so that sterilization and sterilization of microorganisms can be performed efficiently, economically and sufficiently.
  • ozone and other sterilizing properties are also present in places where the washing solution or the culture solution is not in direct contact, such as the upper portion of the culture vessel or inactivation vessel. You It is possible to exert a sterile and sterilizing effect by the gas.
  • the second feature of the present invention is that, as described above, the micro / nano bubble generation device provided in the biological reaction device causes the culture solution containing microorganisms or the like to contain oxygen micro / nano bubbles during the biological reaction.
  • the cleaning solution contains micro / nano bubbles such as ozone.
  • micro-nano bubbles such as ozone
  • sterilization and sterilization action can be exerted by a gas having sterilization properties such as ozone even on a place where the cleaning liquid is not in direct contact, such as the upper part of the culture tank.
  • a means for containing micro-nano bubbles in a culture solution or washing solution containing microorganisms a) means for releasing the micro / nano bubbles into the culture solution containing microorganisms in the culture tank by the micro / nano bubble generator provided outside the culture tank; b) Means for containing micro / nano bubbles in the culture solution supplied to the culture tank by the micro / nano bubble generator provided in the conduit for supplying the culture solution to the culture tank, c) Means for causing the filtrate collected from the culture solution containing microorganisms or the like to contain micro / nano bubbles by a micro / nano bubble generator, and refluxing the filtrate containing the micro / nano bubbles to the culture tank, d) means for supplying a culture solution containing micro-nano bubbles in advance to a culture tank through a conduit; Etc. can be adopted.
  • the means with the least stress and damage to microorganisms is the means b) and d) above.
  • stress and damage are given to microorganisms and the like by the shearing force generated by the release of micro-nano bubbles in the means a) and the shearing force generated during filtration in the means c).
  • micro / nano bubble generating device a known or commercially available device can be used. Specifically, for example, after a sufficient amount of gas is dissolved in a liquid at a certain level of pressure, the pressure is released to create a supersaturated condition of the dissolved gas.
  • a gas-liquid two-phase flow swirl type micro-bubble generator '' that utilizes the phenomenon of generating a vortex by generating a water flow, entraining a large bubble in the vortex, and breaking the vortex into bubbles. Etc. can be used.
  • micro / nano bubble generating apparatus examples include, for example, JP 2007-31690 A, JP 2006-289183 A, JP 2005-245817 A, JP 2007-136255 A, and JP 2009-39600 A. Can be used.
  • the greatest feature of the present invention is that by utilizing this micro / nano bubble generator, oxygen micro / nano bubbles are contained in a culture solution containing microorganisms at the time of biological reaction, and at the time of washing and sterilization after completion of the biological reaction.
  • the cleaning liquid contains micro-nano bubbles such as ozone, but the generation of micro-nano bubbles of oxygen and the generation of micro-nano bubbles such as ozone may be performed by the same micro-nano bubble generator or separate micro-nano bubbles. You may carry out using a nano bubble generator.
  • the supply of the gas containing oxygen and the supply of the gas containing ozone or the like to this device are switched by a switching valve or the like.
  • oxygen containing micro-nano bubbles is contained in a culture solution containing microorganisms or the like during a biological reaction. From the viewpoint of efficiently supplying oxygen necessary for respiration to microorganisms or the like, the oxygen content of the micro-nano bubbles is determined. It is preferable to set it high.
  • the cleaning liquid contains micro-nano bubbles such as ozone, so that cleaning and sterilization are performed economically and sufficiently to the details of the biological reaction device, particularly the filtration membrane. be able to.
  • ozone can be suitably used as the “bactericidal gas such as ozone” contained in micro-nano bubbles such as ozone, but ozone is generally irradiated with a short wavelength ultraviolet ray by a mercury lamp, It can be generated from air or oxygen by low-temperature discharge or the like with high voltage.
  • the amount of ozone supplied to the cleaning liquid varies depending on the type of bacteria to be sterilized, temperature, pH, etc., but it is preferable to supply the ozone concentration in the cleaning liquid to be around 1 ppm. If the ozone concentration in the cleaning liquid is too low, the sterilizing power is insufficient, and in particular, the details of the filtration membrane cannot be sufficiently sterilized. On the other hand, when the ozone concentration in the cleaning liquid is too high, it is not economical, and the inside of the biological reaction apparatus, the filtration membrane, and the like may be deteriorated.
  • the cleaning liquid containing micro-nano bubbles such as ozone
  • water such as ion exchange water, reverse osmosis membrane permeated water, distilled water, and alcohols
  • alcohols include monohydric alcohols such as 1-butanol, 2-butanol and 1-heptanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, diethylene glycol, triethylene glycol, glycerin and the like.
  • butyl cellosolve, phenyl cellosolve and the like are exemplified. Silicone oil or water to which a surfactant is added can also be used.
  • the cleaning solution may be one in which an electrolyte is dissolved in water, or one in which an alkali, an acid, an oxidizing agent, or a reducing agent is added.
  • an additive those that do not adversely affect the filtration membrane, the module member, etc. due to the generation of decomposition products are preferably used.
  • water containing no additive is preferable in that even if it is mixed in the filtrate, the change given to the properties of the filtrate is small.
  • a hydrophobic filtration membrane is used, for example, by immersing the hydrophobic filtration membrane in water-compatible glycerin, or once replacing glycerin with alcohol, glycerin Since water can be replaced with water, water can be selected as the liquid of the hydrophobic filtration membrane.
  • Cleaning and sterilization is usually performed in the following steps. 1) Remove the microorganism used for the biological reaction and the culture solution containing the microorganism from the biological reaction apparatus. 2) A washing liquid is accommodated in the culture tank, and micro-nano bubbles such as ozone are contained in the washing liquid. In addition, the inclusion of micro-nano bubbles such as ozone in the washing liquid is performed as described in a) to d) above.
  • the washing liquid stored in the culture tank, the washing liquid supplied to the culture tank, and the filtration membrane are passed through the filtration tank. This is performed on the washing solution to be refluxed and / or the washing solution before being supplied to the culture tank.
  • the cleaning liquid containing micro-nano bubbles such as ozone is flowed in the same route as the flow of the culture liquid or the filtrate containing microorganisms or the like to clean and sterilize the inside of the biological reaction apparatus.
  • the inside of the biological reaction device can be cleaned and sterilized using the device for carrying out the biological reaction as it is.
  • corners inside the biological reaction apparatus, pores of the filtration membrane, etc. which are difficult to clean and sterilize by ordinary methods, can be sufficiently cleaned and sterilized.
  • the filtration membrane has a large number of pores, and it is difficult to sufficiently sterilize organic substances such as microorganisms clogged in these pores.
  • the cleaning liquid is supplied to the primary side of the filter of the above 1) to 3), and the filtration membrane is cleaned and sterilized by filtering to the secondary side of the filter (hereinafter referred to as “order washing”).
  • order washing filtering to the secondary side of the filter
  • a cleaning liquid containing micro-nano bubbles such as ozone is supplied from a pipe connected to the secondary side of the filter, and the filtration membrane is washed and sterilized by filtering the primary side of the filter. Is to do.
  • the washing liquid after washing and sterilizing the filtration membrane may be discharged to the outside of the biological reaction apparatus, or may be refluxed to the culture tank to wash and sterilize the culture tank. Since the cleaning liquid that has washed and sterilized the filtration membrane in the initial stage of washing contains microorganisms and other organic substances at a high concentration, the cleaning liquid is discharged out of the biological reaction apparatus in the initial stage of washing, and the filtration membrane is sufficiently large. It is preferable that the washing liquid is refluxed to the culture tank and the inside of the culture tank is washed and sterilized at the stage of being washed and sterilized.
  • the washing liquid after washing and sterilizing the filtration membrane may be discharged from the outlet of the filter by one washing and sterilization, or returned to the inlet of the filter and washed and sterilized again.
  • the cleaning liquid that has washed and sterilized the membrane at the initial stage of washing contains microorganisms and other organic substances at a high concentration, so it is discharged from the outlet of the filter. Is preferably returned to the inlet of the filter to clean and sterilize the filter membrane again, since the cleaning solution can be saved.
  • washing and sterilizing the inside of the culture tank with the washing solution it is preferable to spray the washing solution over a wide range like a shower because the inner wall of the cultivation tank can be sufficiently washed and sterilized.
  • Washing and sterilization is performed in a time that can be sufficiently washed and sterilized according to the condition of the filtration membrane and the resistance of microorganisms.
  • the biological reaction apparatus of the present invention and the biological reaction method using this biological reaction apparatus can efficiently and economically perform a biological reaction using microorganisms or the like during a biological reaction.
  • the biological reaction apparatus in particular, the filtration membrane and the like can be cleaned and sterilized efficiently, economically and sufficiently.
  • the biological reaction is carried out with a culture solution containing microorganisms containing oxygen micro-nano bubbles, a porous structure having a high loading density in which microorganisms are supported to the back of the pores. Even when it is used, oxygen necessary for respiration can be sufficiently supplied to microorganisms or the like carried in the back of the pores of the porous structure, so that the efficiency of biological reaction can be improved. In this case, filtration can be performed efficiently and economically, and stress and damage given to microorganisms can be reduced.
  • the biological reaction apparatus of the present invention and the biological reaction method using this biological reaction apparatus can efficiently and economically perform biological reactions using microorganisms using micro-nano bubbles.
  • the present invention is useful not only for the production of foods, chemicals, chemicals and the like using biological reactions such as fermentation, but also for biorefinery for producing bioethanol and the like using biomass.
  • FIG. 1 schematically shows a first embodiment of the biological reaction apparatus of the present invention.
  • the culture tank 1 is provided with a culture tank agitator 17 for stirring the culture solution 6 containing microorganisms and the like.
  • the culture solution 7 supplied to the culture tank 1 to contain micronanobubbles of oxygen by the micro / nano bubble generating device 3 provided in the conduit for supplying the culture solution 7 to the culture tank 1; and b) culturing.
  • the micro / nano bubble generator 2 provided outside the tank 1, the culture liquid 6 containing microorganisms or the like in the culture tank 1 is caused to contain oxygen micro / nano bubbles.
  • the reaction product generated in the culture tank 1 was extracted from the culture tank 1 together with the culture solution 6 containing microorganisms or the like by the culture tank pump 11, and the filtrate and the filtrate were removed in the filter 10. It is separated into a culture solution containing microorganisms (hereinafter referred to as “microorganism concentrate”), and with the valve 12 and valve 13 opened, the filtrate is stored in the filtrate storage tank 16, The concentrated liquid is refluxed to the culture tank 1 through a pipe line.
  • microorganism concentrate a culture solution containing microorganisms
  • the micro-nano bubble generator 3 contains micro-nano bubbles such as ozone in the cleaning liquid supplied to the culture tank 1 instead of the culture liquid 7; and b) the micro-nano bubble generator 2 contains the micro-nano bubble generator 2 in the culture tank 1.
  • the cleaning liquid is made to contain micro-nano bubbles such as ozone.
  • the inside of the culture tank 1 is cleaned and sterilized with a cleaning liquid that sufficiently contains micro-nano bubbles such as ozone.
  • a washing liquid sufficiently containing micro-nano bubbles such as ozone is extracted from the culture tank 1 by the culture tank pump 11, the valve 12 is closed, the valve 13 is opened, and the filtration membrane of the filter 10 is washed and sterilized (in order).
  • the inside of the pipe line of the filter 10 ⁇ the filtrate storage tank 16 is washed and sterilized. If the valve 12 is opened and the valve 13 is closed, the inside of the pipe line of the filter 10 ⁇ the culture tank 1 can be washed and sterilized.
  • the cleaning solution containing micro-nano bubbles such as ozone is distributed to the details of the filter membrane of the filter in the same way as the culture solution and the filtrate. Therefore, it must be thoroughly cleaned and sterilized without placing a burden on the filter membrane. Can do.
  • the concentrates such as microorganisms isolate
  • concentration of microorganisms etc. in the culture tank 1 can be maintained high. .
  • FIG. 2 schematically shows a second embodiment of the biological reaction apparatus of the present invention.
  • the micro / nano bubble generator 4 instead of the micro / nano bubble generators 2 and 3 in the first embodiment, the micro / nano bubble generator 4 is used, and the micronano bubbles are contained in the filtrate of microorganisms or the like and returned to the culture tank 1. It is what you do.
  • the function of selecting whether to discharge from the outlet of the filter or to return to the inlet of the filter when washing and sterilizing Is provided.
  • the functions of 1) and 2) can be provided as appropriate in other embodiments.
  • the culture solution 6 and the filtrate containing microorganisms are removed from the culture tank 1 and the filtrate storage tank 16, respectively.
  • a washing solution is supplied to the culture tank 1 instead of the culture solution 7.
  • the valve 13, valve 14, valve 21, valve 23 and valve 24 are closed, the valve 12 and valve 22 are opened, the culture tank pump 11 is driven, and the filter membrane of the filter 10 is mainly washed.
  • a cleaning liquid containing a high concentration of microorganisms and other organic substances is discharged out of the biological reaction apparatus.
  • the valve 13, valve 14, valve 22, valve 23, and valve 24 are closed, and the culture tank pump 11 is opened by opening the valve 12 and valve 21.
  • the cleaning liquid is guided to the micro / nano bubble generating device 4 through the culture tank 1 ⁇ filter 10 ⁇ valve 12, and the cleaning liquid containing micro / nano bubbles such as ozone is returned to the culture tank 1, thereby forming the cleaning liquid.
  • the inside of the culture tank 1, the filter membrane of the filter 10, the culture tank 1 ⁇ the filter 10 ⁇ the valve 12 ⁇ the micro-nano bubble generator 4 ⁇ the inside of the pipe line of the culture tank 1, etc.
  • the washing liquid sufficiently containing micro-nano bubbles such as ozone is extracted from the culture tank 1 by the culture tank pump 11, the valve 12 and the valve 14 are closed, and the valve 13 is opened.
  • the membrane can be cleaned and sterilized (in order), and the inside of the pipe line of the filter 10 ⁇ the valve 13 ⁇ the filtrate storage tank 16 can be cleaned and sterilized. If the valve 12 and the valve 13 are closed and the valve 14 is opened, the inside of the pipe line of the filter 10 ⁇ the valve 14 ⁇ the culture tank 1 can be washed and sterilized.
  • washing and sterilization can be performed by the same operation as the biological reaction, and sufficient washing and sterilization can be performed without placing a burden on the filtration membrane. it can.
  • the filter 10 Since the micro-nano bubbles are included in the filtrate separated by the filter 10, stress and damage given to microorganisms can be reduced, and the filter 10 Since the concentrated liquid such as microorganisms separated in step 1 is returned to the culture tank 1, the concentration of microorganisms and the like in the culture tank 1 can be maintained high.
  • FIG. 3 schematically shows a third embodiment of the biological reaction apparatus of the present invention.
  • a means for adding micro / nano bubbles to the culture solution 6 containing microorganisms and the like in the culture tank 1 used in the first embodiment is used in the second embodiment.
  • the culture solution 7 supplied to the culture tank 1 is used in combination with means for containing micro / nano bubbles (micro / nano bubble generator 3).
  • FIG. 4 schematically shows a fourth embodiment of the biological reaction apparatus of the present invention.
  • the fourth embodiment is characterized in that a supporting structure 8 in which a microorganism or the like is supported on a porous structure such as a polyvinyl alcohol porous gel is used.
  • the micro-bubbles of oxygen contained in the culture solution at the time of biological reaction and the micro fluid such as ozone in the cleaning solution at the time of cleaning / sterilization after the completion of the biological reaction are performed as follows. Inclusion of nanobubbles is performed.
  • a) The culture solution 7 is supplied to the culture tank 1. b) Opening the valve 12 and closing the valve 13 to drive the culture tank pump 11, leading the filtrate separated by the filter 10 provided in the culture tank 1 to the micro / nano bubble generating device 4, and containing oxygen micro / nano bubbles Then, return to the culture tank 1. c) The reaction product produced in the culture tank 1 is recovered together with the filtrate by opening the valve 13 at an appropriate time, and stored in the filtrate storage tank 16.
  • the culture solution 6 and the filtrate containing microorganisms are removed from the culture tank 1 and the filtrate storage tank 16, respectively.
  • a washing solution is supplied to the culture tank 1 instead of the culture solution 7.
  • the valve 12 is opened, the valve 13 is closed, and the culture tank pump 11 is driven, and the washing liquid is guided to the micro / nano bubble generating device 4 through the pipeline of the culture tank 1 ⁇ the filter 10 ⁇ the valve 12, and micro-bubbles such as ozone are used.
  • the inside of the pipe line of the tank 1 is cleaned and sterilized, and the filter membrane of the filter 10 is cleaned and sterilized (in order).
  • the washing liquid sufficiently containing micro-nano bubbles such as ozone is extracted from the culture tank 1 through the filter 10 by the culture tank pump 11, and the valve 12 and the valve 14 are closed and the valve 13 is opened.
  • the filter membrane of the filter 10 can be washed and sterilized again (in order), and the inside of the pipe line of the filter 10 ⁇ the valve 13 ⁇ the filtrate storage tank 16 can be cleaned and sterilized.
  • the fourth embodiment has the following features by using the supporting structure 8 that supports microorganisms or the like. ⁇ Since the density of microorganisms and the like in the culture tank 1 can be increased, the efficiency of biological reaction can be increased. O It is not necessary to use a microfilter usually used in the technical field of brewing or fermentation as a filter 10 for separating microorganisms from a culture solution 6 containing microorganisms, and an organic polymer such as polyvinylidene fluoride. Since a flat membrane with low filtration accuracy such as a porous membrane made of a compound or a metal wire mesh can be adopted, the filtration step can be carried out economically and efficiently. ⁇ Biological reactions can be carried out efficiently and economically without causing significant stress or damage to microorganisms.
  • FIG. 5 schematically shows a fifth embodiment of the biological reaction apparatus of the present invention.
  • the supporting structure 8 supporting microorganisms or the like in the fourth embodiment is fixed in the culture tank 1 by a fixing member 9 such as a column or a net.
  • oxygen micro-nano bubbles are contained in the culture solution 6 containing microorganisms or the like at the time of biological reaction, and ozone is added to the cleaning solution at the time of cleaning / sterilization after the completion of the biological reaction. Inclusion of micro / nano bubbles is performed in the same manner as in the fourth embodiment.
  • the support structure 8 supporting microorganisms or the like is fixed in the culture tank 1, the support structure 8 is less likely to be damaged or destroyed. Features such as little desorption.
  • FIG. 6 schematically shows a sixth embodiment of the biological reaction apparatus of the present invention.
  • a cleaning liquid containing micro-nano bubbles such as ozone
  • the following operation 1) at the time of a biological reaction similar to the second embodiment and the operation 2 of the forward washing at the time of washing and sterilization are as follows. ) Is performed.
  • the washing liquid containing micro-nano bubbles such as ozone By returning the washing liquid containing micro-nano bubbles such as ozone to the culture tank 1, the inside of the culture tank 1 and the culture tank 1 ⁇ the filter 10 ⁇ the valve 12 ⁇ the micro / nano bubble generator while containing the micro-nano bubbles such as ozone in the washing liquid. 4 ⁇ Wash and sterilize the inside of the pipe of the culture tank 1. c) After that, the washing liquid sufficiently containing micro-nano bubbles such as ozone is extracted from the culture tank 1 by the culture tank pump 11, the valve 12 and the valve 14 are closed, and the valve 13 is opened. The membrane can be cleaned and sterilized (in order), and the inside of the pipe line of the filter 10 ⁇ the valve 13 ⁇ the filtrate storage tank 16 can be cleaned and sterilized. If the valve 12 and the valve 13 are closed and the valve 14 is opened, the inside of the pipe line of the filter 10 ⁇ the valve 14 ⁇ the culture tank 1 can be washed and steriliz
  • the washing and sterilization can be performed by the same operation as the biological reaction, and the washing and sterilization can be sufficiently performed without imposing a burden on the filtration membrane. It is possible to reduce the stress and damage given to the etc., and to maintain a high concentration of microorganisms in the culture tank.
  • the backwashing of the filtration membrane of the following 3) is performed together with the sequential washing of the above 2).
  • the filtration membrane is back-washed by the following steps d) to f).
  • the pump (not shown) is driven to guide the cleaning liquid in the cleaning liquid tank 19 to the micro / nano bubble generating device 5. Then, micro-nano bubbles such as ozone are included in the cleaning liquid.
  • a cleaning liquid containing micro-nano bubbles such as ozone is supplied to the secondary side of the filter 10, filtered to the primary side of the filter 10, and the filter membrane is back-washed for cleaning and sterilization. . f) The washing water after backwashing the filtration membrane is discharged to the outside through the valve 20.
  • the forward washing in 2) and the back washing in 3) are repeated a plurality of times as necessary.
  • the filtration membrane is washed and sterilized because it has a large number of pores, and the washing and sterilization of the filtration membrane, which requires time and effort for washing and sterilization, is performed using both forward washing and backwashing. It has the features that it can be performed sufficiently and the cleaning and sterilization time can be shortened.
  • the third feature of the present invention is that, as described above, after completion of the biological reaction, the culture solution containing the medium such as microorganisms is extracted from the culture tank, and the concentrated solution is separated and concentrated by the separator. Is separated and stored in an inactivation tank, and the concentrated liquid stored in the inactivation tank contains micro-nano bubbles containing a gas having a sterilizing property such as ozone to sterilize microorganisms in the recovered concentrated liquid. It is to be.
  • the third feature of the present invention will be described below with reference to the seventh embodiment.
  • FIG. 7 schematically shows a seventh embodiment of the biological reaction device of the present invention.
  • the reaction product generated in the culture tank 1 with the valve 25 and the valve 27 being closed is transferred from the culture tank pump 11 to the culture solution 6 containing a medium such as microorganisms.
  • it is extracted from the culture tank 1 and separated in the filter 10 into a filtrate containing the reaction product and a concentrated liquid such as microorganisms (hereinafter referred to as “recovered concentrated liquid”).
  • the filtrate is stored in the filtrate storage tank 16, and the recovered concentrated liquid is refluxed to the culture tank 1 through the pipe line.
  • the microorganisms used in the biological reaction are sufficiently sterilized and discharged outside the biological reaction apparatus.
  • the microorganisms are sterilized in the culture tank (hereinafter referred to as “culture tank sterilization”). And a mode in which microorganisms and the like are transferred from the culture tank to the inactivation tank and sterilized (hereinafter referred to as “inactivation tank sterilization”).
  • inactivation tank sterilization can be performed as follows. a) With the valve 27 and the valve 14 closed, the culture solution 6 containing the culture medium such as microorganisms is extracted from the culture vessel 1 by the culture vessel pump 11, and the filter 10 contains the culture solution containing the culture medium. , Separated into recovered concentrate. b) With the valve 12, the valve 13, and the valve 25 opened and the valve 26 closed, the filtrate is stored in the filtrate storage tank 16 and the recovered concentrated liquid is stored in the inactivation tank 30. c) The micro-nano bubble generator 28 contains micro-nano bubbles such as ozone in the recovered concentrated liquid stored in the inactivation tank 30 to sterilize microorganisms. d) When the sterilization of microorganisms or the like is completed, the valve 26 and the valve 33 are opened, and the sterilized recovered concentrated liquid is discharged out of the biological reaction apparatus.
  • culture tank sterilization can be performed as follows. a) With the valve 27 and the valve 25 closed, the culture solution 6 containing the culture medium such as microorganisms is extracted from the culture vessel 1 by the culture vessel pump 11, and the filter 10 contains the filtrate containing the culture medium. , Separated into recovered concentrate. b) While the valve 12, the valve 13 and the valve 14 are opened, the filtrate is stored in the filtrate storage tank 16 and the recovered concentrated liquid is refluxed to the culture tank 1. c) Micro-nano bubbles such as ozone are contained in the collected concentrated liquid stored in the culture tank 1 by the micro-nano bubble generator 29 to sterilize microorganisms. d) When the sterilization of microorganisms or the like is completed, the valve 27 and the valve 33 are opened, the valve 26 is closed, the wastewater pump 32 is driven, and the sterilized recovered concentrated liquid is discharged out of the biological reaction apparatus.
  • the inactivation tank sterilization or the culture tank sterilization can be basically performed by switching the valve 14 and the valve 25, but either the inactivation tank sterilization or the culture tank sterilization can be performed. If it is only necessary to be able to do this, equipment that is not used for sterilization can be omitted. For example, when it is only necessary to sterilize the culture tank, it is not necessary to install equipment on the downstream side of the valve 25 such as the inactivation tank 30 and the micro / nano bubble generator 28.
  • the recovered concentrated liquid is separated using the filter 10 used for recovering the reaction product during the biological reaction, but the recovered concentrated liquid is separated without using a filter medium. It can also be carried out by centrifugation, sedimentation separation or the like utilizing the specific gravity difference.
  • the inactivation tank 30 considers enhancing the sterilization effect of micro-nano bubbles such as ozone, preventing the sterilization gas such as ozone from being discharged out of the bioreactor, etc. It is desirable to use a sealed type.
  • the viscosity of the recovered concentrated liquid is too high, micro-nano bubbles such as ozone will not spread uniformly throughout the recovered concentrated liquid and sterilization of microorganisms will not be performed sufficiently.
  • 30 is preferably provided with a liquid supplier 31 capable of supplying a liquid, and the viscosity of the recovered concentrated liquid is adjusted to an appropriate range.
  • a liquid supplier 31 capable of supplying a liquid, and the viscosity of the recovered concentrated liquid is adjusted to an appropriate range.
  • the biological reaction apparatus basically performs sterilization of the culture tank and / or inactivation tank after the completion of the biological reaction, but when various bacteria are mixed in the culture solution during the biological reaction, the culture tank
  • the valve 27 and the valve 26 are opened, the valve 33 is closed, and the wastewater pump 32 is driven.
  • the culture solution 6 or the concentrated solution in the culture tank 1 can be quickly stored in the inactivation tank 30.
  • micro-nano bubbles such as ozone
  • separation and concentration of microorganisms By sterilizing the collected concentrated liquid, microorganisms and the like can be efficiently, economically and sufficiently sterilized.
  • the present inventors have added a culture solution containing a culture medium such as microorganisms, When the recovered concentrated solution is separated using a separator such as a filter, the ratio of the medium contained in the culture solution entering the recovered concentrated solution is 50% or less, preferably 25% or less.
  • micro-nano bubbles such as ozone
  • the sterilization and sterilization action by micro-nano bubbles can be remarkably enhanced by allowing 50% or more, preferably 75% or more of the medium contained in the culture solution to enter the liquid side of the medium.
  • the ratio of the medium entering the recovered concentrated liquid is reduced to 50% or less, preferably 25% or less by a separator such as a filter, so that the sterilization / sterilization effect is remarkably enhanced. be able to.
  • sterilization and sterilization action is also exerted by a gas having sterilizing properties such as ozone, even on a place where the culture solution is not in direct contact, such as the upper part of the inactivation tank. Can do.
  • micro-nano bubbles such as ozone of the present invention
  • Examples 1 to 4 and Comparative Example 1 the form of bubbles of ozone-containing gas blown into the culture solution and the culture medium (saccharides) Explains the effect of the content of nutrients such as microorganisms such as nitrogen-containing compounds on the sterilization and sterilization action, and uses Examples 5 to 6, such as the upper part of the culture tank where the culture solution does not come into direct contact
  • Examples 5 to 6 such as the upper part of the culture tank where the culture solution does not come into direct contact
  • the sterilization and bactericidal action of micro-nano bubbles such as ozone will be described.
  • Examples 1 to 4 and Comparative Example 1 A 1 L medium bottle (manufactured by Shibata Kagaku, model number: 017200-10002A) is used as a treatment tank, and a culture solution [a standard strain of coryneform bacteria (corynebacterium glutamicum) as a microorganism or the like is turbidity (value of OD660): 16 containing glucose and 24 g / L glucose as well as peptone, yeast extract, etc.].
  • a culture solution a standard strain of coryneform bacteria (corynebacterium glutamicum) as a microorganism or the like is turbidity (value of OD660): 16 containing glucose and 24 g / L glucose as well as peptone, yeast extract, etc.
  • Ozone generator (eco-design made by Model Number: ED-OG-RC12GC) using, ozone concentration 2.2% by weight, making the ozone-containing gas density 1.2kg / m 3, the bubbles of the ozone-containing gas, large In the atmospheric pressure, it was blown into the above-mentioned culture solution at 20 ° C. from the bottom of the treatment tank at an aeration rate of 0.5 L / min.
  • Example 1 Using a micro / nano bubble generator (product name: OK nozzle, model number: OKE-MB200ml), the ozone-containing gas is blown into the culture medium from which the medium has been completely removed in the form of micro / nano bubbles, and 15 minutes at the start of blowing. Thereafter, the number of viable bacteria in the culture solution after 30 minutes, 45 minutes and 60 minutes was measured by a plate culture method.
  • a micro / nano bubble generator product name: OK nozzle, model number: OKE-MB200ml
  • Example 1 The number of viable bacteria was measured in the same manner as in Example 1 except that a silicon tube having an inner diameter of 4 mm was used as an aeration device and ozone-containing gas was blown in the form of a normal bubble.
  • Example 2 The viable cell count was measured in the same manner as in Example 1 except that the culture solution from which 87.5% of the medium was removed was used as the culture solution.
  • Example 3 The viable cell count was measured in the same manner as in Example 1 except that a culture solution from which 75% of the medium was removed was used as the culture solution.
  • Example 4 The viable cell count was measured in the same manner as in Example 1 except that a culture solution from which 50% of the medium was removed was used as the culture solution.
  • Example 1 The results of Examples 1 to 4 and Comparative Example 1 are shown in Table 1.
  • Example 1 When sterilizing and sterilizing microorganisms by blowing ozone-containing gas into a culture solution, compared to the case where the form of bubbles is normal bubbles In the case of micro-nano bubbles, sterilization and sterilization can be remarkably enhanced.
  • the removal rate of the medium is preferably 50% or more, more preferably 75% or more.
  • Examples 5 to 6 In Examples 5 and 6, respectively, in Example 1 and Example 4, at the start of blowing and after 60 minutes, the upper inner surface that does not come in direct contact with the culture solution in the treatment tank was wiped with absorbent cotton and adhered to absorbent cotton. The number of viable bacteria was measured by a plate culture method. The results of Examples 5 to 6 are shown in Table 2.
  • the upper part of the tank such as a culture tank or an inactivation tank
  • Sterilization and sterilization action can be exerted even on a place where the washing solution or culture solution is not in direct contact, and sterilization and sterilization can be performed to every corner of a culture tank, an inactivation tank or the like.

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Abstract

La présente invention aborde le problème de la fourniture d'un bioréacteur dans lequel les micro-organismes ou les cellules utilisés dans une réaction biologique peuvent être minutieusement et économiquement stérilisés/tués après l'achèvement de la réaction biologique. La présente invention concerne également un procédé de réaction biologique qui utilise le bioréacteur. Afin de résoudre le problème susmentionné, le bioréacteur selon la présente invention et le procédé de réaction biologique qui utilise le bioréacteur sont caractérisés en ce que les micro/nano-bulles qui contiennent un gaz microbicide, tel que l'ozone, qui resteront dans un liquide pendant une longue période de temps sont incorporées, après l'achèvement d'une réaction biologique, dans une solution de culture qui contient un milieu de culture et des micro-organismes ou des cellules ou dans un liquide de nettoyage.
PCT/JP2016/051567 2015-01-20 2016-01-20 Bioréacteur doté d'un dispositif pour fournir des micro/nano-bulles contenant de l'oxygène et des micro/nano-bulles contenant un gaz microbicide tel que l'ozone WO2016117599A1 (fr)

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PCT/JP2016/051567 WO2016117599A1 (fr) 2015-01-20 2016-01-20 Bioréacteur doté d'un dispositif pour fournir des micro/nano-bulles contenant de l'oxygène et des micro/nano-bulles contenant un gaz microbicide tel que l'ozone

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JP7135257B2 (ja) 2019-03-05 2022-09-13 エーアールシー メディカル デバイス，インク． 粘性組成物のタンジェンシャルフローろ過のためのシステム及び方法
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KR102615762B1 (ko) 2021-06-22 2023-12-20 (주)에코비즈넷 악취저감 시스템

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