WO2019206207A1

WO2019206207A1 - Active ventilation assembly, active-ventilation-type bioreactor and cell culture device

Info

Publication number: WO2019206207A1
Application number: PCT/CN2019/084203
Authority: WO
Inventors: 韩志强
Original assignee: 上海久博生物工程有限公司
Priority date: 2018-04-26
Filing date: 2019-04-25
Publication date: 2019-10-31
Also published as: CN108315256B; CN108315256A

Abstract

Provided is an active ventilation assembly for a bioreactor and a cell culture device. After being coupled to a biological fermentation or cell culture container, the active ventilation assembly can provide a circulating gas flow passage for active-ventilation-type gas exchange. Further provided are a bioreactor and a cell culture device, which both comprise the active ventilation assembly. The active ventilation assembly and the bioreactor or cell culture device of the present invention can be placed in a carbon dioxide incubator or a tri-gas incubator for use.

Description

活性通气组件以及活性通气式生物反应器和细胞培养器Active ventilation assembly and active aerated bioreactor and cell culture

交叉引用cross reference

本申请要求2018年4月26日提交的、发明名称为“活性通气组件及其活性通气式生物反应器和细胞培养器”的中国专利申请201810386282.1的权益，该申请通过引用而全文并入于此。This application claims the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the disclosure of the entire disclosure of which is hereby incorporated by reference. .

技术领域Technical field

本发明涉及生物材料的制备和处理设备，特别是一种生物反应器和细胞培养器用活性通气组件以及具有该生物反应器和细胞培养器用活性通气组件的细胞培养器和生物反应器。The present invention relates to a preparation and processing apparatus for biological materials, and more particularly to a living ventilator for a bioreactor and a cell culture device, and a cell culture device and a bioreactor having the bioreactor and the active ventilating assembly for the cell culture device.

背景技术Background technique

细胞培养器是用于培养细胞的容器，例如细胞培养瓶、多层板培养瓶、多层细胞培养器、细胞工厂和细胞培养袋(例如，由透气但不透水的膜材料制成)等。细胞培养器可以置于培养箱内，培养箱内的气体预先被配置为适合于细胞培养。细胞培养器内的气体可以与培养箱内的气体进行弥散交换。细胞培养器内的液面通常较低(例如，1-2ml/cm ²)。因此，尽管气体交换方式为弥散交换，无需对细胞培养器内的液体进行搅拌即可实现细胞培养所需的氧气和营养物质的从培养箱内气体的传递。 The cell culture device is a container for culturing cells, such as a cell culture flask, a multi-layer plate culture flask, a multi-layer cell culture device, a cell factory, and a cell culture bag (for example, made of a gas permeable but water-impermeable film material). The cell culture device can be placed in an incubator, and the gas in the incubator is previously configured to be suitable for cell culture. The gas in the cell culture vessel can be exchanged with the gas in the incubator. The level of liquid in the cell culture device is typically low (eg, 1-2 ml/cm ² ). Therefore, although the gas exchange mode is a dispersion exchange, the transfer of oxygen and nutrients from the incubator required for cell culture can be achieved without agitation of the liquid in the cell culture device.

生物反应器是其中生物细胞及其生物活性物质进行化学反应的容器。生物反应器可以置于培养箱内，培养箱内的气体预先被配置为适合于所述化学反应。通常需要驱动生物反应器中的反应液流动，来实现化学反应所需的氧气和营养物质从培养箱内气体的传递。生物反应器可以是悬浮培养式的生物反应器，例如搅拌罐生物反应器、软膜袋生物反应器(例如，由不透气不透水的阻隔性膜材料制成)和气升式生物反应器。A bioreactor is a container in which biological cells and their biologically active substances undergo a chemical reaction. The bioreactor can be placed in an incubator, the gas in the incubator being pre-configured to be suitable for the chemical reaction. It is often desirable to drive the flow of the reaction liquid in the bioreactor to effect the transfer of oxygen and nutrients required for the chemical reaction from the incubator. The bioreactor can be a suspension culture bioreactor such as a stirred tank bioreactor, a soft bag bioreactor (eg, made of a gas impermeable, watertight barrier film material) and an airlift bioreactor.

生物培养箱是在其中进行生物培养(例如细胞培养)或生物反应的实验室设备。生物培养箱包括恒温培养箱、二氧化碳培养箱和三气培养箱。恒温培养箱利用洁净的环境空气进行细胞培养。二氧化碳培养箱利用洁净的环境空气和一定比例的二氧化碳气体进行细胞培养。三气培养箱利用一定比例的洁净O ₂、CO ₂和N ₂的混合气体进行细胞培养。哺乳类动物细胞生长的内环境中，除了氧气外还需要存在一定分压的二氧化碳以保持稳定的pH 以满足细胞的活动。培养箱中气体的二氧化碳含量需要维持在2～10％之间(例如，5％)以保持将在培养液中溶解的二氧化碳的浓度。空气中的二氧化碳浓度很低，如果细胞不在二氧化碳培养箱中培养，则培养液中的HCO ₃-会被耗尽，这样会影响细胞的正常生长。所以绝大多数动物细胞的培养需要二氧化碳培养箱或三气培养箱中进行。因此，实现精确的气体比例配制对于满足细胞的生长是十分重要的。得益于成熟的CO ₂及O ₂传感器技术，生物培养箱一般配备CO ₂和O ₂两种传感器，氮气的浓度是100％-CO ₂浓度-O ₂浓度。 A biological incubator is a laboratory device in which biological culture (e.g., cell culture) or biological reaction is performed. The biological incubator includes a constant temperature incubator, a carbon dioxide incubator, and a three-gas incubator. The constant temperature incubator uses a clean ambient air for cell culture. The carbon dioxide incubator uses a clean ambient air and a certain proportion of carbon dioxide gas for cell culture. The three-gas incubator uses a certain proportion of clean gas mixture of O ₂ , CO ₂ and N ₂ for cell culture. In the internal environment in which mammalian cells grow, in addition to oxygen, a certain partial pressure of carbon dioxide is required to maintain a stable pH to satisfy the activity of the cells. The carbon dioxide content of the gas in the incubator needs to be maintained between 2 and 10% (e.g., 5%) to maintain the concentration of carbon dioxide to be dissolved in the culture solution. The concentration of carbon dioxide in the air is very low. If the cells are not cultured in a carbon dioxide incubator, the HCO ₃ - in the culture solution will be depleted, which will affect the normal growth of the cells. Therefore, the cultivation of most animal cells requires a carbon dioxide incubator or a three-gas incubator. Therefore, achieving accurate gas ratio formulation is important to meet cell growth. Thanks to the mature CO ₂ and O ₂ sensor technology, the biological incubator is generally equipped with two sensors, CO ₂ and O ₂ , and the concentration of nitrogen is 100%-CO ₂ concentration - O ₂ concentration.

为了实现精确的气体比例配置，需要对生物培养箱内的气体进行监测和调控。对于二氧化碳培养箱来说，氧气来自于环境洁净空气，因此不需要测定氧气浓度，只需要测定和控制CO ₂的浓度即可。在二氧化碳培养箱内设置有CO ₂传感器和控制器，以检测箱内的CO ₂浓度，并将检测结果传递给控制器及电磁阀等控制器件。当检测到培养箱内的CO ₂浓度偏低时，就会自动打开电磁阀，使得CO ₂从外部CO ₂气体源(例如，存储有CO ₂的钢瓶)进入箱体内。当CO ₂浓度达到所设置的浓度时，电磁阀关闭。可以利用气体混合泵将箱内底部的CO ₂气体与空气充分混合均匀后，再次注入箱内，从而避免CO ₂的分层或不均匀的现象。 In order to achieve accurate gas ratio configuration, it is necessary to monitor and regulate the gas in the biological incubator. For carbon dioxide incubators, oxygen comes from clean air, so there is no need to measure the oxygen concentration. It is only necessary to measure and control the concentration of CO ₂ . A CO ₂ sensor and a controller are disposed in the carbon dioxide incubator to detect the CO ₂ concentration in the tank, and the detection result is transmitted to a control device such as a controller and a solenoid valve. When it is detected that the CO ₂ concentration in the incubator is low, the solenoid valve is automatically opened, so that the CO ₂ enters the tank from an external CO ₂ gas source (for example, a cylinder in which CO ₂ is stored). When the CO ₂ concentration reaches the set concentration, the solenoid valve closes. The CO ₂ gas at the bottom of the tank can be thoroughly mixed with the air by a gas mixing pump, and then injected into the tank again, thereby avoiding stratification or unevenness of CO ₂ .

二氧化碳培养箱无法提供培养需要高氧(高于22％)或低氧(低于20％)的细胞的气体环境。因此，如果需要进一步控制箱内氧气的浓度，则需要使用三气培养箱。相比于二氧化碳培养箱，三气培养箱是在二氧化碳培养箱的基础上增加了氧气和氮气入口并配置有氧气浓度传感器。氧气浓度传感器可以检测箱内气体环境中的氧气浓度。当检测到箱内的O ₂浓度偏低时，就会自动打开电磁阀，使得O ₂从外部O ₂气体源(例如，存储有O ₂的钢瓶)进入箱体内。当O ₂浓度达到所设置的浓度时，电磁阀关闭。 Carbon dioxide incubators do not provide a gaseous environment for culturing cells that require high oxygen (higher than 22%) or hypoxic (less than 20%). Therefore, if you need to further control the concentration of oxygen in the tank, you need to use a three-gas incubator. Compared to the carbon dioxide incubator, the three-gas incubator adds an oxygen and nitrogen inlet to the carbon dioxide incubator and is equipped with an oxygen concentration sensor. The oxygen concentration sensor detects the concentration of oxygen in the gas environment inside the tank. When it is detected that the concentration of O ₂ in the tank is low, the solenoid valve is automatically opened, so that O ₂ enters the tank from an external source of O ₂ gas (for example, a cylinder in which O ₂ is stored). When the O ₂ concentration reaches the set concentration, the solenoid valve closes.

在通气和气体交换方式上，小型的细胞培养器和生物反应器的气体交换是通过容器盖与容器的开口边缘之间的通气间隙来实现容器的内外气体交换。或者，通过容器盖上的微孔透气滤菌膜来实现容器的内外气体交换。对于细胞培养袋而言，则是通过其自身透气不透水膜的气体弥散来实现袋内外的气体交换。上述这些通气方式为常压下的自行通气。对于较大规模的细胞培养器(譬如40层以上的细胞工厂)、较大规模的搅拌式生物反应器、波浪式软膜生物反应器以及气升式生物反应器，自行通气不能满足其对通气的要求。在这种情况下，需要采用活性通气式(或者称主动通气式)的通气方式，即，通过施加正压，向培养器和反应器内输入含氧高的新鲜气体，同时排出含二氧化碳高的代谢气体。对于与软膜袋生物反应器(例如，波浪式软膜袋生物反应器)而言，除了利用上述活性通气之外，还可以利用活性通气中施加的正压保持软膜袋内的三维内腔。对于气升式生物反应器而言，不论规模大小，均需要采用活性通气，例如，利用从气升式生物反应器的底部鼓入的气体，推动反应液的混合，从而实现气体交换和营养物质的传递。In the venting and gas exchange mode, the gas exchange between the small cell culture device and the bioreactor is to achieve gas exchange between the inside and the outside of the container through the venting gap between the container lid and the open edge of the container. Alternatively, gas exchange between the inside and outside of the container is achieved by a microporous permeable membrane on the lid of the container. In the case of a cell culture bag, gas exchange inside and outside the bag is achieved by gas diffusion of its own gas permeable, water-impermeable film. These ventilation methods are self-ventilating at normal pressure. For larger cell cultures (such as cell plants with more than 40 layers), larger scale agitated bioreactors, waved soft bioreactors, and airlift bioreactors, self-ventilation does not meet their ventilation Requirements. In this case, it is necessary to adopt a reactive ventilation type (or active ventilation type) ventilation method, that is, by applying a positive pressure, a fresh gas containing a high oxygen content is input into the incubator and the reactor, and at the same time, a high carbon dioxide-containing gas is discharged. Metabolic gases. For a soft film bag bioreactor (eg, a waved soft bag bioreactor), in addition to utilizing the above-described active ventilation, the three-dimensional lumen in the soft film bag can be maintained using the positive pressure applied in the active ventilation. . For airlift bioreactors, active ventilation is required regardless of size, for example, by using a gas blasted from the bottom of an airlift bioreactor to promote mixing of the reaction fluids to achieve gas exchange and nutrients. Pass.

现有的活性通气式细胞培养器(如多层细胞培养器-细胞工厂)和生物反应器(如搅拌罐反应器、软膜反应器、气升反应器等)通常是将外部气源的气体(如储气钢瓶内的压缩气体，或气体压缩机产生的气体)经过滤器过滤，测定并混合不同比例的气体成分，然后正压输入细胞培养器或生物反应器内，同时将细胞培养器或生物反应器的内部气体排出。现有的活性通气的特征是全气过滤和一过性排出。为了防止出气管口端的细菌污染，在出气口端也设置有除菌过滤器。现有的活性通气***的需要正压的气源，进气管口端和出气管口端均需要设置死端过滤式除菌过滤器。现有的活性通气***需要O ₂和CO ₂传感器和气体混合器、压力控制器和流量控制器，以确保各种气体比例准确。现有的活性通气***还需要在气体排出口设置加热器，以防止大量带水蒸汽的气体排出时堵塞过滤器的滤膜。因此，现有的细胞培养器和生物反应器的活性通气***不仅价格昂贵而且操作复杂，特别是，不适合小规模(例如培养箱规模)的生物发酵和细胞培养。此外，持续的一过性排出气体，也造成洁净气体的浪费和过滤器的损耗。 Existing active aerated cell culture devices (such as multi-layer cell culture devices - cell factories) and bioreactors (such as stirred tank reactors, soft membrane reactors, gas lift reactors, etc.) are usually gases from external sources. (such as compressed gas in a gas cylinder, or gas produced by a gas compressor) filtered through a filter, measuring and mixing different proportions of gas components, and then positive pressure into the cell culture or bioreactor, while the cell culture or The internal gas of the bioreactor is discharged. Existing active ventilation is characterized by full gas filtration and transient drainage. In order to prevent bacterial contamination at the mouth end of the gas outlet, a sterilizing filter is also provided at the outlet end. In the existing active ventilation system, a positive pressure gas source, a gas inlet nozzle end and an outlet gas port end are required to be provided with a dead end filter type sterilization filter. Existing active ventilation systems require O ₂ and CO ₂ sensors and gas mixers, pressure controllers, and flow controllers to ensure accurate gas ratios. Existing active ventilation systems also require a heater at the gas discharge port to prevent the filter membrane from clogging the large amount of water vapor-exhausted gas. Therefore, the existing cell culture and bioreactor active ventilation systems are not only expensive but also complicated to operate, and in particular, are not suitable for biological fermentation and cell culture on a small scale (for example, an incubator scale). In addition, the continuous transient exhaust gas also causes waste of clean gas and loss of the filter.

本发明利用现有设备(例如，二氧化碳培养箱，三气培养箱)实现对气体比例的精确调控，并利用蠕动泵实现气体的非介入、无污染输送，提供了活性通气装置和具有该活性通气装置的活性通气式生物反应器和细胞培养器，以解决现有的一过性排出式的活性通气生物反应器和细胞培养器需要昂贵复杂的气体调控***和复杂操作的问题。The invention utilizes existing equipment (for example, a carbon dioxide incubator, a three-gas incubator) to achieve precise regulation of the gas ratio, and uses a peristaltic pump to achieve non-invasive, non-contaminated transport of the gas, provides an active ventilation device and has the active ventilation The device's active aerated bioreactors and cell culturers address the problems of expensive and complex gas regulation systems and complex operations in existing transient venting reactive venting bioreactors and cell culturers.

发明内容Summary of the invention

鉴于现有技术的缺点，本发明提供了一种生物反应器和细胞培养器用活性通气组件及利用该生物反应器和细胞培养器用活性通气组件的细胞培养器和生物反应器。本发明利用了现有设备(例如，二氧化碳培养箱，三气培养箱)实现对气体比例的精确调控，并利用蠕动泵实现气体的无污染输送，从而无需单独且复杂昂贵的气体过滤器、CO ₂及O ₂传感器和控制器、气体混合器、压力和流量控制***。本发明的活性通气组件及利用该活性通气组件的活性通气式细胞培养器和生物反应器能够节省气体，且不需要气体流量控制***。 In view of the disadvantages of the prior art, the present invention provides a living ventilator for a bioreactor and a cell culturer, and a cell culture and bioreactor using the bioreactor and the active ventilator for the cell culture device. The invention utilizes existing equipment (for example, a carbon dioxide incubator, a three-gas incubator) to achieve precise regulation of the gas ratio, and utilizes a peristaltic pump to achieve gas-free transportation of the gas, thereby eliminating the need for a separate and complicated expensive gas filter, CO. ₂ and O ₂ sensors and controllers, gas mixers, pressure and flow control systems. The active ventilating assembly of the present invention and the active aerated cell culture and bioreactor utilizing the active venting assembly are capable of saving gas and do not require a gas flow control system.

在一个方面，本发明提供了一种生物反应器和细胞培养器用活性通气组件。该活性通气组件包括一个或多个气体交换器，该一个或多个气体交换器中的每一个具有内部空间，并配置为在所述内部空间和所述内部空间之外的外部空间之间进行气体交换；以及管线，该管线在一个或多个容器和所述一个或多个气体交换器之间气密地耦合，从而形成气体流动回路，其中在所述一个或多个容器中设置有生物发酵或细胞培养的物料和/或产物。所述管线的至少一部分配置为适于由气体驱动装置驱动，使得气体在所述气体流动回路中沿着预设气体流动方向流动。所述气体沿着所述预设气体流动方向依次经过所述气体驱动装置、所述容器、所述一个或多个气体交换器并返回所述气体驱动装置。In one aspect, the invention provides a reactive venting assembly for a bioreactor and cell culture. The reactive venting assembly includes one or more gas exchangers, each of the one or more gas exchangers having an interior space and configured to be disposed between the interior space and an exterior space outside of the interior space a gas exchange; and a line that is hermetically coupled between the one or more vessels and the one or more gas exchangers to form a gas flow loop, wherein the one or more vessels are provided with a living being Fermentation or cell culture materials and/or products. At least a portion of the line is configured to be adapted to be driven by a gas drive such that gas flows in the gas flow circuit in a predetermined gas flow direction. The gas passes sequentially through the gas drive, the vessel, the one or more gas exchangers, and back to the gas drive in the predetermined gas flow direction.

在一些实例中，本发明的活性通气组件还包括一个或多个接口装置。该一个或多个接口装置配置为分别与所述一个或多个容器气密地耦合。所述接口装置包括至少两个开口，该至少两个开口中的两个开口分别与所述管线气密地耦合。所述接口装置还可以包括允许所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器的开口。所述开口在未进行所述生物物质进入和/或移出所述容器期间保持气密封闭。所述接口装置可以包括延伸进入所述容器内部的进气管和出气管，所述进气管和出气管分别与所述管线气密地耦合，并且其中所述进气管延伸进入所述容器内部的长度与所述出气管延伸进入所述容器内部的长度不同。例如，所述进气管延伸进入所述容器内部的长度大于所述出气管延伸进入所述容器内部的长度。在一些情况下，所述进气管延伸进入所述容器内部的部分包括柔性管，该柔性管上设置有一个或多个通孔，以允许气体从所述通孔排出。In some examples, the active venting assembly of the present invention further includes one or more interface devices. The one or more interface devices are configured to be hermetically coupled to the one or more containers, respectively. The interface device includes at least two openings, two of the at least two openings being hermetically coupled to the pipeline, respectively. The interface device may also include an opening that allows the biological fermentation or cell culture material and/or product to enter and/or remove the container. The opening remains hermetically sealed during the absence of the biological material entering and/or removing the container. The interface device may include an intake pipe and an air outlet pipe extending into the interior of the container, the intake pipe and the air outlet pipe being hermetically coupled to the pipeline, respectively, and wherein the intake pipe extends into the interior of the container The length of the outlet pipe extending into the interior of the container is different. For example, the length of the inlet tube extending into the interior of the container is greater than the length of the outlet tube extending into the interior of the container. In some cases, the portion of the intake tube that extends into the interior of the container includes a flexible tube that is provided with one or more through holes to allow gas to escape from the through hole.

在一些实例中，所述管线可以直接与所述容器气密地耦合，从而形成所述气体流动回路。In some examples, the line can be hermetically coupled directly to the vessel to form the gas flow circuit.

在一些实例中，所述一个或多个气体交换器中的至少一个可以包括一个或多个膜。所述膜包括多个孔，所述孔的孔径被配置为允许所述气体交换并阻止细菌通过。所述一个或多个气体交换器中的所述至少一个可以具有框架，并且所述一个或多个膜覆盖所述框架的至少一部分。所述一个或多个气体交换器中的所述至少一个还可以包括至少一个保护层，该保护层设置在所述膜之外。In some examples, at least one of the one or more gas exchangers can include one or more membranes. The membrane includes a plurality of apertures configured to allow the gas to exchange and prevent passage of bacteria. The at least one of the one or more gas exchangers may have a frame and the one or more membranes cover at least a portion of the frame. The at least one of the one or more gas exchangers may further include at least one protective layer disposed outside the membrane.

在一些实例中，所述一个或多个气体交换器可以包括多个气体交换器，该多个气体交换器通过所述管线彼此并联或串联。在一些实例中，所述一个或多个气体交换器中的至少一个具有气体入口和气体出口，其中在所述气体入口和气体出口之间限定气流通道，该气体通道的方向与所述预设气体流动方向一致，并且其中所述气体入口和所述气体出口分别与所述管线气密地耦合。所述气体入口和所述气体出口可以彼此相邻地设置。所述气体入口和所述气体出口可以彼此相远离地设置。In some examples, the one or more gas exchangers can include a plurality of gas exchangers that are connected in parallel or in series with each other through the lines. In some examples, at least one of the one or more gas exchangers has a gas inlet and a gas outlet, wherein an air flow passage is defined between the gas inlet and the gas outlet, the direction of the gas passage being opposite to the preset The gas flows in a uniform direction, and wherein the gas inlet and the gas outlet are each hermetically coupled to the pipeline. The gas inlet and the gas outlet may be disposed adjacent to each other. The gas inlet and the gas outlet may be disposed away from each other.

在一些实例中，所述预设气体流动方向与所述气体交换的方向基本上彼此正交。In some examples, the predetermined gas flow direction and the direction of gas exchange are substantially orthogonal to each other.

在一些实例中，所述气体驱动装置可以包括蠕动泵，所述蠕动泵配置为交替地挤压和松弛所述管线的所述至少一部分，从而使得气体在所述气体流动回路中沿着所述预设气体流动方向流动。在一些实例中，活性通气组件还可以包括气压调节装置，该气压调节装置设置在所述气体流动回路中，并与所述管线气密地耦合。所述气压调节装置可以设置在所述容器和所述一个或多个气体交换器之间。所述气压调节装置可以配置为改变和/In some examples, the gas drive device can include a peristaltic pump configured to alternately squeeze and relax the at least a portion of the line such that gas is along the gas flow circuit The flow of the preset gas flows. In some examples, the reactive vent assembly can also include a gas pressure regulating device disposed in the gas flow circuit and hermetically coupled to the line. The air pressure adjusting device may be disposed between the container and the one or more gas exchangers. The air pressure adjusting device can be configured to change and /

在另一个方面，本发明提供了一种主动式气体循环***，包括如本发明一个方面所提供的活性通气组件，以及所述一个或多个容器。所述容器可以包括瓶、软袋或细胞工厂中的一种或多种。In another aspect, the invention provides an active gas circulation system comprising an active venting assembly as provided in one aspect of the invention, and the one or more containers. The container may comprise one or more of a bottle, a soft bag or a cell factory.

在一些实例中，气体循环***还包括一个或多个接口装置。该一个或多个接口装置配置为分别与所述一个或多个容器气密地耦合。所述接口装置包括至少两个开口，该至少两个开口中的两个开口分别与所述管线气密地耦合。所述接口装置还包括允许所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器的开口。所述开口在未进行所述生物物质进入和/或移出所述容器期间保持气密封闭。所述接口装置可以包括延伸进入所述容器内部的进气管和出气管，所述进气管和出气管分别与所述管线气密地耦合。所述进气管延伸进入所述容器内部的长度与所述出气管延伸进入所述容器内部的长度不同。例如，所述进气管延伸进入所述容器内部的长度可以大于所述出气管延伸进入所述容器内部的长度。在一些实例中，所述进气管延伸进入所述容器内部的部分包括柔性管，该柔性管上设置有一个或多个通孔，以允许气体从所述通孔排出。In some examples, the gas circulation system also includes one or more interface devices. The one or more interface devices are configured to be hermetically coupled to the one or more containers, respectively. The interface device includes at least two openings, two of the at least two openings being hermetically coupled to the pipeline, respectively. The interface device also includes an opening that allows the biological fermentation or cell culture material and/or product to enter and/or remove the container. The opening remains hermetically sealed during the absence of the biological material entering and/or removing the container. The interface device may include an intake pipe and an air outlet pipe that extend into the interior of the container, the intake and exhaust pipes being hermetically coupled to the pipeline, respectively. The length of the inlet tube extending into the interior of the container is different than the length at which the outlet tube extends into the interior of the container. For example, the length of the inlet tube extending into the interior of the container may be greater than the length of the outlet tube extending into the interior of the container. In some examples, the portion of the intake tube that extends into the interior of the container includes a flexible tube that is provided with one or more through holes to allow gas to escape from the through hole.

在一些实例中，所述所述管线可以直接与所述容器气密地耦合，从而形成所述气体流动回路。所述容器上还可以设有允许所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器的开口。In some examples, the line can be hermetically coupled directly to the vessel to form the gas flow circuit. The container may also be provided with openings for allowing the bio-fermentation or cell culture material and/or product to enter and/or remove the container.

在一些实例中，所述一个或多个气体交换器中的至少一个包括一个或多个膜。所述膜包括多个孔，所述孔的孔径被配置为允许所述气体交换并阻止细菌通过。所述一个或多个气体交换器中的所述至少一个可以具有框架，并且其中所述一个或多个膜覆盖所述框架的至少一部分。所述一个或多个气体交换器中的所述至少一个还可以包括至少一个保护层，该保护层设置在所述膜之外。In some examples, at least one of the one or more gas exchangers includes one or more membranes. The membrane includes a plurality of apertures configured to allow the gas to exchange and prevent passage of bacteria. The at least one of the one or more gas exchangers can have a frame, and wherein the one or more membranes cover at least a portion of the frame. The at least one of the one or more gas exchangers may further include at least one protective layer disposed outside the membrane.

在一些实例中，所述一个或多个气体交换器包括多个气体交换器，该多个气体交换器通过所述管线彼此并联或串联。在一些实例中，所述一个或多个气体交换器中的至少一个具有气体入口和气体出口。在所述气体入口和气体出口之间限定气流通道，该气体通道的方向与所述预设气体流动方向一致。所述气体入口和所述气体出口分别与所述管线气密地耦合。所述气体入口和所述气体出口可以彼此相邻地设置或彼此相远离地设置。所述预设气体流动方向与所述气体交换的方向基本上彼此正交。In some examples, the one or more gas exchangers comprise a plurality of gas exchangers that are connected in parallel or in series with one another via the lines. In some examples, at least one of the one or more gas exchangers has a gas inlet and a gas outlet. An air flow passage is defined between the gas inlet and the gas outlet, the direction of the gas passage being coincident with the predetermined gas flow direction. The gas inlet and the gas outlet are each hermetically coupled to the line. The gas inlet and the gas outlet may be disposed adjacent to each other or away from each other. The predetermined gas flow direction and the direction of the gas exchange are substantially orthogonal to each other.

在一些实例中，所述气体驱动装置可以包括蠕动泵。所述蠕动泵配置为交替地挤压和松弛所述管线的所述至少一部分，从而使得气体在所述气体流动回路中沿着所述预设气体流动方向流动。In some examples, the gas drive can include a peristaltic pump. The peristaltic pump is configured to alternately compress and relax the at least a portion of the line such that gas flows in the gas flow circuit along the predetermined gas flow direction.

在一些实例中，气体循环***还包括气压调节装置，该气压调节装置设置在所述气体流动回路中，并与所述管线气密地耦合。所述气压调节装置可以设置在所述容器和所述一个或多个气体交换器之间。所述气压调节装置可以配置为改变和/或保持所述管线的管径，从而改变和/或保持所述管线内的气体的压力。In some examples, the gas circulation system further includes a gas pressure regulating device disposed in the gas flow circuit and hermetically coupled to the gas line. The air pressure adjusting device may be disposed between the container and the one or more gas exchangers. The gas pressure regulating device can be configured to change and/or maintain the diameter of the line to change and/or maintain the pressure of the gas within the line.

在一些实例中，气体循环***还包括控制器。该控制器与所述气体驱动装置通信地耦合，并配置为根据所述气体流动回路中的压力来调节所述气体驱动装置的操作。所述气体流动回路中的所述压力可以是在所述管线或所述容器处测量的。所述气体流动回路中的所述压力可以是采用非接触方式测量的。In some examples, the gas circulation system also includes a controller. The controller is communicatively coupled to the gas drive and configured to adjust operation of the gas drive based on pressure in the gas flow circuit. The pressure in the gas flow circuit can be measured at the line or the vessel. The pressure in the gas flow circuit can be measured in a non-contact manner.

在一些实例中，所述一个或多个容器包括多个容器，该多个容器通过所述管线彼此并联或串联。In some examples, the one or more containers include a plurality of containers that are connected to each other in parallel or in series by the pipeline.

在另一个方面，本发明提供了一种活性通气组件。所述的活性通气组件包括内部气流通道相连通的至少三部分元件：气体交换器、蠕动泵泵管和导气管。所述气体交换器为具有内部气流通道且串联连通于导气管两管段之间的腔体，所述腔体的至少一个壁面上密封设置有允许气体透过以实现腔体内外气体交换但阻挡细菌透过的微孔透气滤菌膜。所述蠕动泵泵管为蠕动泵泵头管卡和挤压驱动其内部气体流动的弹性软管管段。所述导气管为连通所述蠕动泵泵管与所述气体交换器之间以及二者分别与待用的生物反应器或细胞培养器的进气管和出气管之间的气体传输管道。In another aspect, the invention provides an active venting assembly. The active venting assembly includes at least three components in communication with an internal gas flow passage: a gas exchanger, a peristaltic pump tubing, and an airway. The gas exchanger is a cavity having an internal gas flow passage and is connected in series between the two pipe sections of the air pipe, and at least one wall surface of the cavity is sealed to allow gas to permeate to realize gas exchange inside and outside the cavity but block bacteria Through the microporous permeable membrane. The peristaltic pump tube is a peristaltic pump head tube card and an elastic hose tube section that squeezes and drives the internal gas flow. The air conduit is a gas transmission conduit that communicates between the peristaltic pump tube and the gas exchanger and between the intake and outlet tubes of the bioreactor or cell culture device to be used, respectively.

在一些实例中，所述气体交换器为由两层所述的微孔透气滤菌膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体。所述微孔透气滤菌袋的两端融合有连通管嘴。所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。在一些实例中，所述气体交换器为由两层所述的微孔透气滤菌膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体。所述微孔透气滤菌袋的一端融合有两个连通管嘴，两个连通管嘴之间的两层软膜向袋内融合延伸形成与两个连通管嘴相连通的U形气流通道。所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。In some examples, the gas exchanger is a microporous gas permeable filter bag cavity having an internal gas flow passage fused from two layers of the microporous gas permeable membrane. Both ends of the microporous permeable filter bag are fused with a connecting nozzle. The connecting nozzle and the air guiding tube are connected by a tight fit or an integrated fusion. In some examples, the gas exchanger is a microporous gas permeable filter bag cavity having an internal gas flow passage fused from two layers of the microporous gas permeable membrane. One end of the microporous gas permeable filter bag is fused with two communicating nozzles, and two soft films between the two communicating nozzles are fused to the bag to form a U-shaped air flow channel communicating with the two communicating nozzles. The connecting nozzle and the air guiding tube are connected by a tight fit or an integrated fusion.

在一些实例中，所述气体交换器为设置有透气滤菌膜密封的透气窗的两层阻隔性软膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体。所述微孔透气滤菌袋两端融合有连通管嘴，所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。In some examples, the gas exchanger is a microporous gas permeable bag cavity having an internal gas flow passage fused by a two-layer barrier film provided with a gas permeable membrane sealed venting window. The microporous permeable filter bag is fused with a connecting nozzle at both ends, and the connecting nozzle and the air guiding tube are connected by a tight fit or an integrated fusion.

在一些实例中，所述气体交换器为设置有透气滤菌膜密封的透气窗的两层阻隔性软膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体。所述微孔透气滤菌袋的一端融合有两个连通管嘴。两个连通管嘴之间的两层软膜向袋内融合延伸形成与两个连通管嘴相连通的U形气流通道。所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。In some examples, the gas exchanger is a microporous gas permeable bag cavity having an internal gas flow passage fused by a two-layer barrier film provided with a gas permeable membrane sealed venting window. One end of the microporous permeable filter bag is fused with two connecting nozzles. The two layers of soft film between the two communicating nozzles extend into the pocket to form a U-shaped air flow passage that communicates with the two communicating nozzles. The connecting nozzle and the air guiding tube are connected by a tight fit or an integrated fusion.

在一些实例中，所述气体交换器为两端带连接管嘴的硬质材料的支撑框架上密封融合有所述微孔透气滤菌膜而成的硬质骨架腔体。所述连通管嘴与导气管之间通过紧密配合连接。In some examples, the gas exchanger is a rigid frame cavity formed by sealing a microporous gas permeable membrane on a support frame of a hard material having a connection nozzle at both ends. The communication nozzle and the air guiding tube are connected by a close fit.

在一些实例中，所述微孔透气滤菌膜的外面附设有带通气孔网起支持保护微孔透气滤菌膜作用的网孔片。In some examples, a mesh sheet with a vent mesh to support the protection of the microporous permeable membrane is attached to the outside of the microporous membrane.

在一些实例中，所述的导气管通过三通接头或多通接头并联或串联连通两个或以上气体交换器以增加气体交换效率，或并联或串联连通两个或以上的生物反应器或细胞培养器以增加培养规模。In some examples, the air conduits connect two or more gas exchangers in parallel or in series through a three-way joint or a multi-way joint to increase gas exchange efficiency, or to connect two or more bioreactors or cells in parallel or in series. The incubator is used to increase the size of the culture.

在一些实例中，所述的导气管在气体交换器与所述生物反应器或细胞培养器的出气管之间的管段上设置有通过调节管径大小而调节所述生物反应器或细胞培养器内部气压的气压调节器。In some examples, the airway tube is disposed on a pipe section between the gas exchanger and the gas pipe of the bioreactor or cell culture device to adjust the bioreactor or cell culture device by adjusting the size of the pipe diameter. Air pressure regulator for internal air pressure.

在一些实例中，所述的活性通气式生物反应器配置有本发明的一个方面提供的活性通气组件。所述的生物反应器为波浪式生物反应器、气升式生物反应器、摇瓶生物反应器或搅拌式生物反应器。所述生物反应器上设置有供气体进出的进气管和出气管。所述活性通气组件的导气管与所述生物反应器的进气管和出气管相连通形成气流通道闭合环路。In some examples, the reactive aerated bioreactor is configured with an active venting assembly provided by one aspect of the invention. The bioreactor is a wave bioreactor, an airlift bioreactor, a shake flask bioreactor or a stirred bioreactor. The bioreactor is provided with an intake pipe and an outlet pipe for gas to enter and exit. The air duct of the active ventilating assembly communicates with the intake and outlet tubes of the bioreactor to form a closed loop of the air flow passage.

在一些实例中，所述生物反应器为软膜生物反应器。所述软膜生物反应器为由2层软膜融合而成的平面(2D)软膜生物反应器，或三维(3D)软膜生物反应器。所述三维软膜生物反应器为其融合圈内的2层软膜中至少1层软膜的表面积大于融合圈所围成的平面面积5％以上。In some examples, the bioreactor is a soft membrane bioreactor. The soft membrane bioreactor is a planar (2D) soft membrane bioreactor or a three-dimensional (3D) soft membrane bioreactor fused by two layers of soft membrane. The three-dimensional soft membrane bioreactor has a surface area of at least one soft film of the two soft films in the fusion ring which is larger than a plane area enclosed by the fusion ring by 5% or more.

在一些实例中，所述的软膜生物反应器的进气管和出气管贯通融合于所述软膜反应器的两层软膜的融合边，或贯通融合于平面软膜上，或贯通融合于软膜袋的管口所配置的管口盖上。所述贯通融合于管口盖的进气管和出气管分别设置于不同的管口盖或同一管口盖。设置于同一管口盖的进气管和出气管延伸入管口内或反应器内不同的深度。In some examples, the inlet and outlet tubes of the soft membrane bioreactor are fused to the fusion side of the two layers of the soft membrane reactor, or are fused to the planar soft membrane, or are fused to The nozzle of the soft film bag is placed on the nozzle cover. The intake pipe and the outlet pipe that are fused to the nozzle cover are respectively disposed on different nozzle covers or the same nozzle cover. The intake and outlet tubes disposed in the same nozzle cover extend into the nozzle or at different depths within the reactor.

在一些实例中，所述软膜生物反应器为通过摇动驱使内部液体形成波浪而实现液体混合和气体交换的波浪式软膜生物反应器。所述软膜生物反应器为通过向其内部反应液曝气而实现液体混合和气体交换的气升式软膜生物反应器。所述气升式软膜生物反应器的进气管在袋内连通设置有延伸至反应器底部带细小的曝气孔的曝气管。In some examples, the soft membrane bioreactor is a waved soft membrane bioreactor that achieves liquid mixing and gas exchange by shaking the internal liquid to form a wave. The soft membrane bioreactor is an airlift type soft membrane bioreactor that achieves liquid mixing and gas exchange by aeration to a reaction liquid inside thereof. The air intake pipe of the airlift type soft membrane bioreactor is connected in the bag with an aeration pipe extending to a small aeration hole at the bottom of the reactor.

在一些实例中，所述的活性通气式细胞培养器配置有根据本发明的一个方面提供的活性通气组件。所述的细胞培养器为单层细胞培养容器-培养瓶或多层的硬质塑料细胞培养容器-细胞工厂。所述单层或多层的硬质塑料细胞培养器具有一个或多个培养器管口。所述培养器管口上配置有管口盖。在所述管口盖上贯通设置有进气管或/和出气管。所述进气管和出气管可设置于同一管口盖或分别设置于不同的管口盖。设置于同一管口盖的进气管和出气管延伸入管口内或反应器内不同的深度。所述活性通气组件的导气管分别与细胞培养器的进气管和出气管通过相连通形成气流通道的闭合环路。In some examples, the reactive aerated cell culture device is configured with an active venting assembly provided in accordance with an aspect of the invention. The cell culture device is a single-layer cell culture vessel-culture flask or a multi-layered rigid plastic cell culture vessel-cell factory. The single or multi-layered rigid plastic cell culture device has one or more incubator nozzles. A nozzle cover is disposed on the mouth of the incubator. An intake pipe or/and an air outlet pipe are disposed through the nozzle cover. The intake pipe and the outlet pipe may be disposed on the same nozzle cover or respectively disposed on different nozzle covers. The intake and outlet tubes disposed in the same nozzle cover extend into the nozzle or at different depths within the reactor. The air duct of the active ventilator assembly is in communication with the inlet and outlet tubes of the cell culture device to form a closed loop of the air flow passage.

根据下面的具体实施方式，本公开的其他方面和优点对于本领域技术人员来说将变得容易理解，其中仅示出和描述了本公开的说明性实施方式。如将认识到的那样，本公开能够具有其他和不同的实施方式，并且其若干细节能够在各个明显的方面进行修改，所有这些都没有脱离本公开。因此，附图和说明书本质上被认为是说明性的，而不是限制性的。Other aspects and advantages of the present disclosure will be readily apparent to those skilled in the <RTIgt; The present disclosure is capable of other and different embodiments, and may be Accordingly, the drawings and description are to be regarded as

附图说明DRAWINGS

本发明的新颖特征在随附权利要求书中具体阐明。通过参考以下对其中利用到本发明原理的说明性实施方式加以阐述的具体实施方式和附图(本文亦称为“图”)将会更好地理解本发明的特征和优势。The novel features of the invention are set forth in the appended claims. The features and advantages of the present invention will become more apparent from the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

图1是本发明的活性通气组件的示例性实施例的结构示意图。1 is a schematic structural view of an exemplary embodiment of an active ventilation assembly of the present invention.

图2是本发明的活性通气组件的又一示例性实施例的结构示意图。2 is a schematic structural view of still another exemplary embodiment of the active ventilation assembly of the present invention.

图3是具有本发明的活性通气组件的生物反应器或细胞培养器的实施例的结构示意图。3 is a schematic illustration of the structure of an embodiment of a bioreactor or cell culture device having an active venting assembly of the present invention.

图4是本发明的气体交换器的示例性实施例的结构示意图。4 is a schematic structural view of an exemplary embodiment of a gas exchanger of the present invention.

图5是本发明的气体交换器的又一示例性实施例的结构示意图。Fig. 5 is a schematic structural view of still another exemplary embodiment of the gas exchanger of the present invention.

图6是本发明的气体交换器的又一示例性实施例的结构示意图。Fig. 6 is a schematic structural view of still another exemplary embodiment of the gas exchanger of the present invention.

图7是本发明的气体交换器的又一示例性实施例的结构示意图。Fig. 7 is a schematic structural view of still another exemplary embodiment of the gas exchanger of the present invention.

图8是本发明的气体交换器的又一示例性实施例的结构示意图。Figure 8 is a schematic structural view of still another exemplary embodiment of the gas exchanger of the present invention.

图9是本发明的气体交换器的又一示例性实施例的结构示意图。Figure 9 is a schematic structural view of still another exemplary embodiment of the gas exchanger of the present invention.

图10是本发明的气体交换器的又一示例性实施例的结构示意图。Figure 10 is a schematic view showing the structure of still another exemplary embodiment of the gas exchanger of the present invention.

图11是本发明的接口装置的示例性实施例的结构示意图。Figure 11 is a block diagram showing an exemplary embodiment of an interface device of the present invention.

图12是本发明的生物反应器的使用的示例性实施例的示意图。Figure 12 is a schematic illustration of an exemplary embodiment of the use of the bioreactor of the present invention.

图13是本发明的生物反应器的又一实施例的结构示意图。Figure 13 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention.

图14是本发明的生物反应器的使用的示例性实施例的使用示意图。Figure 14 is a schematic illustration of the use of an exemplary embodiment of the use of the bioreactor of the present invention.

图15是本发明的生物反应器的又一实施例的结构示意图。Figure 15 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention.

图16是本发明的生物反应器的又一实施例的结构示意图。Figure 16 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention.

图17是本发明的生物反应器的又一实施例的结构示意图。Figure 17 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention.

图18是本发明的细胞培养器的示例性实施例的结构示意图。Figure 18 is a schematic structural view of an exemplary embodiment of a cell culture device of the present invention.

图19为本发明的细胞培养器的又一示例性实施例的结构示意图。Figure 19 is a schematic view showing the structure of still another exemplary embodiment of the cell culture device of the present invention.

图20为本发明的活生物反应器和细胞培养器的使用状态示意图。Figure 20 is a schematic view showing the state of use of the living bioreactor and the cell culture device of the present invention.

具体实施方式detailed description

本发明提供了一种生物反应器和细胞培养器用活性通气组件，其适合于与现有的生物反应器或细胞培养器配合使用。在与生物反应器或细胞培养器耦接后，该活性通气组件可以提供封闭的气体流动回路。本发明还提供了一种包括活性通气组件的生物反应器以及细胞培养器。至少本发明的活性通气组件、生物反应器或细胞培养器的气体交换器可以放置在二氧化碳培养箱或三气培养箱内进行气体交换。二氧化碳培养箱或三气培养箱具有的传感器***和气体成分设定及保持***可以保证二氧化碳培养箱或三气培养箱内的气体环境的稳定。通过本发明的活性通气组件，可以实现在生物反应器或细胞培养器的内部气体与二氧化碳培养箱或三气培养箱内的气体环境之间的主动式气体交换，从而确保生物反应器和细胞培养器内的气体保持期望的成分。The present invention provides a reactive venting assembly for bioreactors and cell cultures that is suitable for use with existing bioreactors or cell culture vessels. The active venting assembly can provide a closed gas flow circuit after being coupled to the bioreactor or cell culture device. The invention also provides a bioreactor comprising a reactive venting assembly and a cell culture device. At least the gas exchanger of the active venting module, bioreactor or cell culture device of the present invention can be placed in a carbon dioxide incubator or a three gas incubator for gas exchange. The sensor system and gas composition setting and holding system of the carbon dioxide incubator or the three-gas incubator can ensure the stability of the gas environment in the carbon dioxide incubator or the three-gas incubator. The active gas exchange module of the present invention can realize active gas exchange between the internal gas of the bioreactor or the cell culture device and the gas environment in the carbon dioxide incubator or the three gas incubator, thereby ensuring the bioreactor and cell culture. The gas inside the device maintains the desired composition.

本发明提供的活性通气组件以及采用该活性通气组件的生物反应器和细胞培养器实现了循环式气体交换。通过活性通气组件中的气体交换器，实现细胞培养器或生物反应器内外的气体成分(例如O ₂和CO ₂)的交换，从而节省气体，大大降低了对于气源的消耗。由于利用了现有生物培养箱实现对气体环境的温度、湿度和气体配置的精确控制，因此无需设置昂贵的气体传感设备，也无需设置复杂的压力、流量控制***和气体过滤***。此外，细胞培养器或生物反应器内的培养液不蒸发，也不会堵塞滤膜。 The active ventilating assembly provided by the present invention and the bioreactor and cell culture device using the active venting assembly achieve a cyclic gas exchange. The exchange of gas components (such as O ₂ and CO ₂ ) inside and outside the cell culture or bioreactor is achieved by a gas exchanger in the active venting assembly, thereby saving gas and greatly reducing the consumption of the gas source. Thanks to the use of existing bio incubators for precise control of the temperature, humidity and gas configuration of the gaseous environment, there is no need to set up expensive gas sensing equipment or complex pressure, flow control systems and gas filtration systems. In addition, the culture solution in the cell culture or bioreactor does not evaporate and does not clog the filter.

图1为本发明的生物反应器和细胞培养器用活性通气组件的示例性实施例的结构示意图。在一些实施例中，活性通气组件包括气体交换器1和导气管3(即，管线***)。气体交换器1和导气管3气密地耦合。导气管可以包括多个节段，而非必须是一条连续的管线。例如，导气管的一个节段可以气密地耦接到气体交换器的进气端，而另一个节段可以气密地耦接到气体交换器的出气端，从而使得导气管与气体交换器整体上提供气体流动通路。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic view showing the structure of an exemplary embodiment of a living ventilating assembly for a bioreactor and a cell culture device of the present invention. In some embodiments, the active venting assembly includes a gas exchanger 1 and an airway tube 3 (ie, a line system). The gas exchanger 1 and the air guiding tube 3 are hermetically coupled. The airway tube can include multiple segments instead of having to be a continuous line. For example, one segment of the air conduit can be hermetically coupled to the intake end of the gas exchanger, while the other segment can be hermetically coupled to the gas outlet of the gas exchanger, thereby allowing the gas conduit and gas exchanger The gas flow path is provided as a whole.

在一些实例中，导气管3可以包括蠕动泵泵管2。该蠕动泵泵管2包括弹性软管，适合于被例如蠕动泵泵头挤压，使得该蠕动泵泵管内部的气体流动。蠕动泵泵管2与导气管3的其他部分可以由相同或不同的材料制成。蠕动泵泵管的材质具有一定弹性。此外，蠕动泵泵管的材质具有耐磨、承压能力、硬度、气密、低吸附、耐高温、不易老化、不溶胀、抗腐蚀、低析出物等性质。蠕动泵泵管的材料可以包括硅橡胶、氟橡胶、特氟龙、橡胶、塑料、合成材料等。在附图1所示的实施例中，蠕动泵泵管2与导气管3的其他部分可以通过连接接头34相连通，从而使得蠕动泵泵管2是可更换的。In some examples, the airway tube 3 can include a peristaltic pump tube 2. The peristaltic pump tube 2 comprises an elastic hose adapted to be squeezed by, for example, a peristaltic pump head such that gas flows inside the peristaltic pump tube. The peristaltic pump tube 2 and other portions of the airway tube 3 may be made of the same or different materials. The material of the peristaltic pump tube has a certain elasticity. In addition, the material of the peristaltic pump tube has the characteristics of wear resistance, pressure bearing capacity, hardness, airtightness, low adsorption, high temperature resistance, aging resistance, non-swelling, corrosion resistance, and low precipitation. The material of the peristaltic pump tube may include silicone rubber, fluororubber, Teflon, rubber, plastic, synthetic materials, and the like. In the embodiment shown in Figure 1, the peristaltic pump tubing 2 and other portions of the airway tube 3 can be communicated through a connector 34 such that the peristaltic pump tubing 2 is replaceable.

图2为本发明的活性通气组件的又一示例性实施例的结构示意图。与图1所示的活性通气组件不同的是，蠕动泵泵管2和导气管3的其他部分之间为一体化连接。蠕动泵泵管2和导气管3的其他部分可以由相同的材料制成，例如蠕动泵泵管2和导气管3的其他部分同为弹性软管。这里，仅从功能上定义蠕动泵泵管与导气管的其他部分的区别。即蠕动泵泵头所夹持的弹性软管段为蠕动泵泵管。2 is a schematic view showing the structure of still another exemplary embodiment of the active ventilation assembly of the present invention. Unlike the active venting assembly shown in Figure 1, the peristaltic pump tubing 2 and the other portions of the airway tube 3 are integrally connected. The peristaltic pump tube 2 and other portions of the airway tube 3 may be made of the same material, for example, the peristaltic pump tube 2 and other portions of the air tube 3 are also elastic hoses. Here, only the difference between the peristaltic pump tube and other parts of the air tube is functionally defined. That is, the elastic hose section clamped by the pump head of the peristaltic pump is a peristaltic pump pump tube.

气体交换器1与导气管3串联地耦接。气体交换器1具有内部空间，并在其中实现内部气流通道。气体交换器1配置为在内部空间与内部空间之外的外部空间之间实现气体交换。在一些实例中，气体交换器1配置为在实现气体交换时，阻止外部空间的细菌和灰尘进入内部空间。在一些实施例中，气体交换器可以包括微孔透气滤菌膜。微孔透气滤菌膜具有多个微孔，微孔的尺寸设置为在允许气体自由通过的同时，阻挡细菌和灰尘的通过。所述气体交换器内的气体流动方向可以基本上垂直于所述微孔透气滤菌膜。The gas exchanger 1 is coupled in series with the gas conduit 3. The gas exchanger 1 has an internal space in which an internal gas flow passage is realized. The gas exchanger 1 is configured to effect gas exchange between the internal space and an external space outside the internal space. In some examples, the gas exchanger 1 is configured to prevent bacteria and dust from the external space from entering the interior space when gas exchange is achieved. In some embodiments, the gas exchanger can include a microporous gas permeable membrane. The microporous gas permeable membrane has a plurality of micropores sized to block the passage of bacteria and dust while allowing free passage of gas. The gas flow direction within the gas exchanger may be substantially perpendicular to the microporous gas permeable membrane.

利用气体交换器1的内部的气体成分与气体交换器1的外部的气体成分的不同而导致的分压差，实现该气体成分透过微孔透气滤菌膜的气体交换。该气体交换确保了气体交换器1的内部的气体成分与外部的气体成分一致。例如，如果气体交换器1的内部气体环境中的CO ₂气体含量大于气体交换器1的外部气体环境中的CO ₂气体含量，则气体交换器1的内部的CO ₂气体将透过微孔透气滤菌膜传排出到气体交换器1的外部。例如，如果气体交换器1的内部气体环境中的O ₂气体含量小于气体交换器1的外部气体环境中的O ₂气体含量，则气体交换器1的外部的O ₂气体将透过微孔透气滤菌膜进入到气体交换器1的内部。以这种方式，可以使得经由导气管而持续地流过气体交换器1的内部空间的气体的成分与气体交换器1的外部空间的气体环境的成分保持一致。 The gas exchange of the gas component through the microporous gas permeable membrane is achieved by the difference in partial pressure caused by the difference between the gas component inside the gas exchanger 1 and the gas component outside the gas exchanger 1. This gas exchange ensures that the gas component inside the gas exchanger 1 coincides with the external gas component. For example, if the CO ₂ gas content of CO ₂ gas content of the gas exchanger of the internal gaseous environment a gas exchanger is greater than 1 atmosphere outside, the inside of the gas exchanger 1 CO ₂ gas through the microporous breathable The filter membrane is discharged to the outside of the gas exchanger 1. For example, if the content of O ₂ gas O ₂ gas content of the gas atmosphere inside the exchanger 1 is less than the external atmosphere gas exchanger 1, the external gas exchange of the O ₂ gas permeable microporous breathable 1 The filter membrane enters the inside of the gas exchanger 1. In this way, the composition of the gas continuously flowing through the inner space of the gas exchanger 1 via the air conduit can be made to coincide with the composition of the gaseous environment of the outer space of the gas exchanger 1.

可以通过增大气体交换器的微孔透气滤菌膜的表面积，实现气体交换器的内部气体与外部气体的充分交换。还可以通过设置多个气体交换器实现气体的充分交换，如下文详细所述。微孔透气滤菌膜可以是疏水性微孔滤膜，例如聚四氟乙烯PTFE疏水通气过滤膜。疏水性微孔滤膜上的孔的孔径可以是0.01μm、0.02μm、0.05μm、0.07μm、0.09μm、0.1μm、0.22μm、0.3μm、0.45μm或者上述任何两个值之间的值。微孔透气滤菌膜可以具有透气性、不透水性、阻燃性、耐高温、抗强酸碱、无毒等性质。The internal exchange of the gas and the external gas of the gas exchanger can be achieved by increasing the surface area of the microporous membrane of the gas exchanger. It is also possible to achieve a full exchange of gases by providing a plurality of gas exchangers, as described in detail below. The microporous gas permeable membrane may be a hydrophobic microporous membrane, such as a polytetrafluoroethylene PTFE hydrophobic vent membrane. The pore size of the pores on the hydrophobic microporous membrane may be 0.01 μm, 0.02 μm, 0.05 μm, 0.07 μm, 0.09 μm, 0.1 μm, 0.22 μm, 0.3 μm, 0.45 μm or a value between any two of the above values. The microporous gas permeable membrane can have the properties of gas permeability, water impermeability, flame retardancy, high temperature resistance, strong acid and alkali resistance, non-toxicity and the like.

在一些实施例中，活性通气组件还可以包括接口装置。接口装置可以气密地耦接到与活性通气组件配合的容器，如下文详细所述。In some embodiments, the active ventilation assembly can also include an interface device. The interface device can be hermetically coupled to the container that mates with the active venting assembly, as described in detail below.

图3是具有本发明的活性通气组件的生物反应器或细胞培养器的实施例的结构示意图。容器5可以是任何形状、体积或材料的生物反应器或细胞培养器，例如瓶或者袋。在附图2所示的实施例中，如容器5可以是平面软膜波浪生物反应器。平面软膜波浪生物反应器由两层平面软膜形成，在上层软膜上融合有反应器管口，而两层膜在周边融合从而形成融合圈32。Figure 3 is a schematic illustration of the construction of an embodiment of a bioreactor or cell culture device having an active venting assembly of the present invention. The container 5 can be a bioreactor or cell culturer of any shape, volume or material, such as a bottle or bag. In the embodiment shown in Figure 2, the container 5 can be a planar soft film wave bioreactor. The planar soft-film wave bioreactor is formed by two layers of planar soft membranes, on which the reactor nozzles are fused, and the two membranes are fused at the periphery to form a fusion ring 32.

在一些实例中，接口装置11可以包括与容器的开口端相配合的管口盖。管口盖可以螺纹地或者以其他方式气密地耦接到容器的开口。在一些实例中，管口盖可以是插塞，该插塞可以气密地***容器的开口。接口装置11上至少贯通地设置有开口12和开口13。开口12和开口13分别与导气管气密地耦接。开口12可以是进气口。开口13可以是出气口。在一些实例中，接口装置11上可以设有进气管12和出气管13。进气管12和出气管13分别与导气管气密地耦接。在一些实施例中，接口装置11上还设置有供生物样品进入和/或离开生物反应器5的开口。In some examples, the interface device 11 can include a nozzle cover that mates with the open end of the container. The spout can be threaded or otherwise airtightly coupled to the opening of the container. In some examples, the spout can be a plug that can be airtightly inserted into the opening of the container. The interface device 11 is provided with an opening 12 and an opening 13 at least penetratingly. The opening 12 and the opening 13 are hermetically coupled to the air duct, respectively. The opening 12 can be an air inlet. The opening 13 can be an air outlet. In some examples, the inlet device 12 and the outlet pipe 13 may be provided on the interface device 11. The intake pipe 12 and the air outlet pipe 13 are airtightly coupled to the air guide tubes, respectively. In some embodiments, the interface device 11 is also provided with an opening for the biological sample to enter and/or exit the bioreactor 5.

导气管3耦合至接口装置11和气体交换器1，从而形成从接口装置11到气体交换器1、再到接口装置11的气体流动回路。导气管3的至少一部分配置为适于由气体驱动装置驱动，从而使得气体在气体流动回路中流动。气体驱动装置可以是蠕动泵或压缩机。导气管3的蠕动泵泵管2可以嵌设于蠕动泵泵头6的卡槽内。电机驱动器17驱动蠕动泵的转子18旋转。转子18上设置有辊轮19。转子18的旋转带动辊轮19反复挤压蠕动泵泵管2，从而驱动蠕动泵泵管2内部的气体通过导气管3向容器内流动。The air conduit 3 is coupled to the interface device 11 and the gas exchanger 1 to form a gas flow circuit from the interface device 11 to the gas exchanger 1 to the interface device 11. At least a portion of the airway tube 3 is configured to be adapted to be driven by a gas drive such that gas flows in the gas flow circuit. The gas drive can be a peristaltic pump or a compressor. The peristaltic pump tube 2 of the airway tube 3 can be embedded in the card slot of the peristaltic pump head 6. The motor driver 17 drives the rotor 18 of the peristaltic pump to rotate. A roller 19 is disposed on the rotor 18. The rotation of the rotor 18 drives the roller 19 to repeatedly press the peristaltic pump pump tube 2, thereby driving the gas inside the peristaltic pump tube 2 to flow into the container through the air guiding tube 3.

在一些实例中，在气体交换器1与出气口13之间的导气管3上，还可以设置有气压调节器4。在一些实例中，气压调节器4配置为通过调节导气管3的内径，保持生物反应器5的鼓起状态并调整保持生物反应器5的内部气压。该气压调节器可以设置有压力传感器，用来测量所述导气管内的气体压力。可以根据所测量的气体压力控制气体驱动装置的操作。例如，如果所测量的气体压力小于预设值，则可以控制增大蠕动泵的转速。还可以以非接触式方式测量所述容器内或管线内的气体压力。例如，可以设置非接触式压力测量装置，通过向平面软膜生物反应器的表面上喷射气体并测量反射的气体的压力，测量出平面软膜生物反应器内的气体压力。本领域技术人员可以理解，容器中的气体压力与导气管内的气体压力是基本上一致的。In some examples, a gas pressure regulator 4 may also be provided on the air conduit 3 between the gas exchanger 1 and the gas outlet 13. In some examples, the gas pressure regulator 4 is configured to maintain the bulging state of the bioreactor 5 and adjust the internal gas pressure of the bioreactor 5 by adjusting the inner diameter of the air tube 3. The gas pressure regulator may be provided with a pressure sensor for measuring the gas pressure in the air guiding tube. The operation of the gas drive can be controlled based on the measured gas pressure. For example, if the measured gas pressure is less than a preset value, the increase in the rotational speed of the peristaltic pump can be controlled. It is also possible to measure the gas pressure in the vessel or in the pipeline in a non-contact manner. For example, a non-contact pressure measuring device can be provided to measure the gas pressure in the planar soft membrane bioreactor by injecting gas onto the surface of the planar soft membrane bioreactor and measuring the pressure of the reflected gas. Those skilled in the art will appreciate that the gas pressure in the vessel is substantially consistent with the gas pressure within the airway.

如附图3所示，在活性通气组件和容器中，形成循环的气体流动回路。在气体驱动装置的驱动下，气体在气体流动回路中沿着预设的方向循环流动。例如，气体沿着所述预设气体流动方向，从容器出发，依次经过气体交换器、气体驱动装置并返回容器。气体交换器可以设置在容器的下游，使得由气体驱动装置驱动的气体首先被送入容器，而从容器中离开的气体进入气体交换器进行成分交换。As shown in Figure 3, a circulating gas flow circuit is formed in the active venting assembly and vessel. Driven by the gas drive, the gas circulates in a predetermined direction in the gas flow circuit. For example, the gas proceeds from the vessel along the predetermined gas flow direction, passes through the gas exchanger, the gas drive, and returns to the vessel. The gas exchanger may be disposed downstream of the vessel such that gas driven by the gas drive is first fed to the vessel and gas exiting the vessel enters the gas exchanger for component exchange.

在一些实例中，所述容器可以是与气体输送装置分离的。本发明的气体输送装置可以与市售的容器配合使用。例如，本发明的气体输送装置的输气管的两个端部可以***容器的盖，从而实现气体输送装置与容器的气体连通。例如，本发明的气体输送装置可以具有接口装置。该接口装置是与容器相配合的适配器，诸如插塞或旋盖。气体输送装置的输气管的两个端部可以与接口装置气密地耦合。通过将接口装置与容器气密地耦合，气体输送装置实现与容器的气体连通。在一些实例中，所述容器可以是与气体输送装置一体提供的。例如，气体输送装置的输气管的两个端部一体地耦接到容器，从而实现与容器的气体连通。在容器上，还可以提供用于生物材料进入/移出的开口。生物材料的非限制性实施例可以包括细胞、细菌、真菌或生物体。In some examples, the container may be separate from the gas delivery device. The gas delivery device of the present invention can be used in conjunction with commercially available containers. For example, both ends of the gas delivery tube of the gas delivery device of the present invention can be inserted into the lid of the container to effect gas communication between the gas delivery device and the container. For example, the gas delivery device of the present invention can have an interface device. The interface device is an adapter that mates with the container, such as a plug or a screw cap. Both ends of the gas delivery tube of the gas delivery device can be hermetically coupled to the interface device. The gas delivery device effects gas communication with the container by hermetically coupling the interface device to the container. In some examples, the container may be provided integrally with a gas delivery device. For example, the two ends of the gas delivery tube of the gas delivery device are integrally coupled to the container to effect gas communication with the container. On the container, an opening for the entry/exit of biological material can also be provided. Non-limiting examples of biological materials can include cells, bacteria, fungi, or organisms.

图4至图10示出了本发明的气体交换器的示例性实施例。在一个示例性实施例中，如图4所示，气体交换器1包括支撑框8和设置在支撑框8的相对两侧上的膜9。支撑框8可以呈扁盒形状。支撑框8可以是一体化热塑成型的。支撑框8在纵向两端上具有连接管嘴7，上述导气管3耦接至连接管嘴7。两个连接管嘴7限定了气体交换器1的内部气流通道，该内部气流通道与上述气体流动回路一致。该内部气流通道基本上垂直于膜。膜9可以是微孔透气滤菌膜。微孔透气滤菌膜的面积可以与流经气体交换器1的内部气流通道的气体的流量和/或流速相匹配，从而实现气体交换器内部与外部的充分气体交换。4 through 10 illustrate an exemplary embodiment of a gas exchanger of the present invention. In an exemplary embodiment, as shown in FIG. 4, the gas exchanger 1 includes a support frame 8 and a membrane 9 disposed on opposite sides of the support frame 8. The support frame 8 can be in the shape of a flat box. The support frame 8 can be integrally thermoformed. The support frame 8 has a connection nozzle 7 at both longitudinal ends, and the air guide tube 3 is coupled to the connection nozzle 7. The two connecting nozzles 7 define an internal gas flow passage of the gas exchanger 1, which is identical to the gas flow circuit described above. The internal gas flow passage is substantially perpendicular to the membrane. The membrane 9 may be a microporous permeable membrane. The area of the microporous gas permeable membrane can be matched to the flow rate and/or flow rate of the gas flowing through the internal gas flow path of the gas exchanger 1, thereby achieving sufficient gas exchange between the interior and exterior of the gas exchanger.

在一些实例中，可以设置具有增大的面积的微孔透气滤菌膜，从而使得流经气体交换器1的内部气流通道的气体能够与气体交换器1的外部的气体环境充分交换，实现气体交换器1的内部和外部的气体成分一致。在一些实例中，可以设置多个气体交换器1，从而实现流经气体交换器1的内部气流通道的气体与外部气体环境的充分交换。多个气体交换器1既可以通过通气管彼此串联连接，也可以彼此并联连接。例如，通气管可以设置有三接口，从而实现三个气体交换器的并联连接。In some examples, a microporous gas permeable membrane having an increased area may be provided such that gas flowing through the internal gas flow path of the gas exchanger 1 can be fully exchanged with the gas environment outside the gas exchanger 1, achieving gas The gas composition inside and outside of the exchanger 1 is identical. In some instances, a plurality of gas exchangers 1 may be provided to achieve sufficient exchange of gas flowing through the internal gas flow passages of the gas exchanger 1 with the external gaseous environment. The plurality of gas exchangers 1 may be connected to each other in series via a vent pipe or may be connected in parallel to each other. For example, the vent tube can be provided with three interfaces to achieve a parallel connection of the three gas exchangers.

在另一个示例性实施例中，如图5所示，气体交换器1还设置有在微孔透气滤菌膜9上设置的网孔片10。网孔片10可以是透气的保护膜。该网孔片10可以支持并保护微孔透气滤菌膜9。In another exemplary embodiment, as shown in FIG. 5, the gas exchanger 1 is further provided with a mesh sheet 10 provided on the microporous gas permeable membrane 9. The mesh sheet 10 may be a gas permeable protective film. The mesh sheet 10 can support and protect the microporous gas permeable membrane 9.

在另一个示例性实施例中，如图6所示，气体交换器1包括支撑框8。支撑框8可以呈圆筒状。支撑框8可以是一体化热塑成型的。在支撑框的圆周壁上设置有连接管嘴7，上述导气管3耦接至连接管嘴7。支撑框的圆周壁上的两个连接管嘴7限定了气体交换器1的内部气流通道，该内部气流通道与上述气体流动回路一致。该内部气流通道基本上垂直于膜。在支撑框8的筒端面上密封地设置有微孔透气滤菌膜。在微孔透气滤菌膜上还可以设有网孔片10，从而支持并保护微孔透气滤菌膜。In another exemplary embodiment, as shown in FIG. 6, the gas exchanger 1 includes a support frame 8. The support frame 8 may have a cylindrical shape. The support frame 8 can be integrally thermoformed. A connecting nozzle 7 is disposed on the circumferential wall of the support frame, and the air guiding tube 3 is coupled to the connecting nozzle 7. The two connecting nozzles 7 on the circumferential wall of the support frame define an internal gas flow passage of the gas exchanger 1, which is identical to the gas flow circuit described above. The internal gas flow passage is substantially perpendicular to the membrane. A microporous gas permeable membrane is sealingly disposed on the end surface of the tube of the support frame 8. A mesh sheet 10 may also be provided on the microporous gas permeable membrane to support and protect the microporous membrane.

在另一个示例性实施例中，如图7所示，气体交换器1包括支撑框8。支撑框8可以呈圆筒状。支撑框8可以是一体化热塑成型。在支撑框的筒端壁上设置有连接管嘴7，上述导气管3耦接至连接管嘴7。支撑框的筒端壁上的两个连接管嘴7限定了气体交换器1的内部气流通道，该内部气流通道与上述气体流动回路一致。该内部气流通道基本上垂直于膜。在支撑框8的筒周面上密封地设置有微孔透气滤菌膜。在微孔透气滤菌膜上还可以设有网孔片10，从而支持并保护微孔透气滤菌膜。In another exemplary embodiment, as shown in FIG. 7, the gas exchanger 1 includes a support frame 8. The support frame 8 may have a cylindrical shape. The support frame 8 can be an integral thermoplastic. A connecting nozzle 7 is disposed on the end wall of the support frame, and the air guiding tube 3 is coupled to the connecting nozzle 7. The two connecting nozzles 7 on the barrel end wall of the support frame define an internal gas flow passage of the gas exchanger 1, the internal gas flow passage being identical to the gas flow circuit described above. The internal gas flow passage is substantially perpendicular to the membrane. A microporous gas permeable membrane is sealingly disposed on the circumferential surface of the support frame 8. A mesh sheet 10 may also be provided on the microporous gas permeable membrane to support and protect the microporous membrane.

在另一个示例性实施例中，如图8所示，气体交换器可以不具有支撑框。例如，气体交换器1可以是由两个所述微孔透气滤菌膜9制成的微孔透气滤菌膜袋。可以将该两个微孔透气滤菌膜9的边缘热压合在一起而形成所述袋。所述微孔透气滤菌膜袋可以是矩形、圆形、椭圆形或者其他任何形状。在所述微孔透气滤菌膜袋的纵向相对的两侧可以设置有连通管嘴7。两个连接管嘴7限定了气体交换器1的内部气流通道，该内部气流通道与上述气体流动回路一致。该内部气流通道基本上垂直于微孔透气滤菌膜9。In another exemplary embodiment, as shown in Figure 8, the gas exchanger may not have a support frame. For example, the gas exchanger 1 may be a microporous gas permeable membrane bag made of two of the microporous gas permeable membranes 9. The edges of the two microporous permeable membranes 9 can be thermocompression bonded together to form the pouch. The microporous gas permeable membrane bag may be rectangular, circular, elliptical or any other shape. A communication nozzle 7 may be disposed on both longitudinally opposite sides of the microporous gas permeable membrane bag. The two connecting nozzles 7 define an internal gas flow passage of the gas exchanger 1, which is identical to the gas flow circuit described above. The internal gas flow passage is substantially perpendicular to the microporous gas permeable membrane 9.

在另一个示例性实施例中，如图9所示，气体交换器1为微孔透气滤菌膜袋。该微孔透气滤菌膜袋可以不具有支撑框。该微孔透气滤菌膜袋可以包括两个带有窗口的软膜。可以将该两个软膜的边缘热压合在一起而形成所述袋。该袋可以具有任何适合的形状和几何尺寸。所述软膜的窗口区域可以是圆形、矩形、椭圆形或其他任何适宜的形状。在所述软膜的窗口区域，设置有微孔透气滤菌膜9。微孔透气滤菌膜9可以压合至软膜的所述窗口区域的内边缘。例如，在软膜的所述窗口区域的内边缘与微孔透气滤菌膜9的重叠区域，可以形成融合边33。在所述微孔透气滤菌膜袋的纵向相对的两侧可以设置有连通管嘴7。两个连接管嘴7限定了气体交换器1的内部气流通道，该内部气流通道与上述气体流动回路一致。该内部气流通道基本上垂直于微孔透气滤菌膜9。In another exemplary embodiment, as shown in FIG. 9, the gas exchanger 1 is a microporous gas permeable membrane bag. The microporous gas permeable membrane bag may not have a support frame. The microporous gas permeable membrane bag may comprise two soft membranes with a window. The edges of the two pellicles can be thermocompression bonded together to form the pouch. The bag can have any suitable shape and geometry. The window region of the soft film may be circular, rectangular, elliptical or any other suitable shape. In the window region of the soft film, a microporous gas permeable membrane 9 is provided. The microporous gas permeable membrane 9 can be pressed to the inner edge of the window region of the soft film. For example, a fusion edge 33 may be formed in an overlapping region of the inner edge of the window region of the soft film and the microporous gas permeable membrane 9. A communication nozzle 7 may be disposed on both longitudinally opposite sides of the microporous gas permeable membrane bag. The two connecting nozzles 7 define an internal gas flow passage of the gas exchanger 1, which is identical to the gas flow circuit described above. The internal gas flow passage is substantially perpendicular to the microporous gas permeable membrane 9.

在如图10所示的另一个示例性实施例中，与上述附图9所示的实施例不同的是，所述软膜的窗口区域为U形，并在所述微孔透气滤菌膜袋的同一侧上设置有两个连通管嘴7，使得这两个连通管嘴7彼此邻近。两个连通管嘴7分别与U形的微孔透气滤菌膜9内的内部气流通道相连通。在附图10所示的实施例中，气体交换器1的内部气流通道形成为U形。该U形的内部气流通道增大了内部气流通道的长度，增强了气体透过微孔透气滤菌膜的气体交换效果。该内部气流通道基本上垂直于微孔透气滤菌膜9。。In another exemplary embodiment as shown in FIG. 10, unlike the embodiment shown in FIG. 9 described above, the window region of the soft film is U-shaped, and the microporous permeable membrane is Two communication nozzles 7 are provided on the same side of the bag such that the two communication nozzles 7 are adjacent to each other. The two communication nozzles 7 are respectively in communication with the internal air flow passages in the U-shaped microporous gas permeable membrane 9. In the embodiment shown in Fig. 10, the internal air flow passage of the gas exchanger 1 is formed in a U shape. The U-shaped internal gas flow passage increases the length of the internal gas flow passage and enhances the gas exchange effect of the gas passing through the microporous gas permeable membrane. The internal gas flow passage is substantially perpendicular to the microporous gas permeable membrane 9. .

图11为本发明的接口装置的示例性实施例的结构示意图。接口设备11可以是与容器相耦合的管口盖。例如，管口盖可以是插塞。插塞上可以设置有凸起的环，与生物反应器的开口端相配合，从而实现与容器的气密耦合。例如，管口盖可以是螺纹盖。螺纹盖上可以设置有与生物反应器的开口端的内螺纹相配合的外螺纹，从而实现与容器的气密耦合。在接口设备11上可以贯通地设置有进气管12和出气管13。进气管12和出气管13在管口盖内延伸的长度可以不同，从而防止发生气体的短路。即，防止从进气管12进入容器的气体在未与容器内气体充分混合的情况下从出气管13排出。例如，进气管12在管口盖内延伸的深度可以大于出气管13在管口盖内延伸的长度。在一些实施例中，进气管12可以延伸到生物反应器中的液面以下，从而使得由蠕动泵泵送的气体充分与生物反应器内的液体接触。在其它的实施中，可以设置有多个管口盖11，进气管12和出气管13可以分别设置在两个不同的管口盖上。管口盖11上还可以设置有供生物材料进入/离开生物反应器的开口。Figure 11 is a block diagram showing an exemplary embodiment of an interface device of the present invention. The interface device 11 can be a nozzle cover that is coupled to the container. For example, the nozzle cover can be a plug. A plug ring may be provided on the plug to cooperate with the open end of the bioreactor to achieve a gas-tight coupling with the container. For example, the spout can be a threaded cap. The threaded cap may be provided with an external thread that cooperates with the internal thread of the open end of the bioreactor to achieve a gas-tight coupling with the container. An intake pipe 12 and an air outlet pipe 13 are provided through the interface device 11. The length of the intake pipe 12 and the air outlet pipe 13 extending within the nozzle cover may be different to prevent a short circuit of the gas from occurring. That is, the gas that has entered the container from the intake pipe 12 is prevented from being discharged from the air outlet pipe 13 without being sufficiently mixed with the gas in the container. For example, the depth of the air intake tube 12 extending within the nozzle cover may be greater than the length of the air outlet tube 13 extending within the nozzle cover. In some embodiments, the intake manifold 12 can extend below the level of liquid in the bioreactor such that the gas pumped by the peristaltic pump is sufficiently in contact with the liquid within the bioreactor. In other implementations, a plurality of nozzle covers 11 may be provided, and the intake pipe 12 and the air outlet pipe 13 may be respectively disposed on two different nozzle covers. An opening for the biomaterial to enter/exit the bioreactor may also be provided on the spout lid 11.

图12为本发明的生物反应器的使用的示例性实施例的示意图。如附图12所示，本发明的波浪式软膜生物反应器(例如附图1所示的生物反应器)可以放置在在摇床上。例如将软膜生物反应器固定于固定框夹14内，然后置于摇床16的平台15上。可以将蠕动泵泵头6安装到摇床的蠕动泵驱动器上，并将蠕动泵泵管2卡固于蠕动泵泵头6的卡槽内。摇床平台15的摇动驱动软膜生物反应器内部的培养液体形成波浪，从而在软膜生物反应器内实现气体与液体的充分交换和混合。在蠕动泵的驱动下，软膜生物反应器内部的气体被泵送至气体交换器1内。在分压差的作用下，气体交换器1的内部空间中的气体与气体交换器1的外部空间中的外部气体环境实现跨微孔透气滤菌膜9的气体交换。气体交换器1外的高氧分压的O ₂进入气体交换器1内，而气体交换器1内的高二氧化碳分压的CO ₂则弥散到气体交换器1外。在气体交换器1与出气管13之间的导气管3上，还可以设置气压调节器4。气压调节器4可以调整导气管3的内径，从而调整软膜生物反应器的鼓起状态和内部压力。摇床、软膜生物反应器和气体交换器可以置于二氧化碳培养箱或三气培养箱内。可以利用培养箱的气体调控***实现对培养箱内气体环境的温度、湿度、压力和成分的精确控制和保持。进而，通过气体交换器1的气体交换，实现对生物反应器内的氧气和二氧化碳成分的精确调控。 Figure 12 is a schematic illustration of an exemplary embodiment of the use of a bioreactor of the present invention. As shown in Figure 12, the waved soft membrane bioreactor of the present invention (e.g., the bioreactor shown in Figure 1) can be placed on a shaker. For example, the membrane bioreactor is fixed in the fixed frame clamp 14 and then placed on the platform 15 of the shaker 16. The peristaltic pump head 6 can be mounted to the peristaltic pump actuator of the shaker and the peristaltic pump tubing 2 can be snapped into the slot of the peristaltic pump head 6. The shaking of the shaker platform 15 drives the culture liquid inside the soft membrane bioreactor to form a wave, thereby achieving full exchange and mixing of the gas and the liquid in the soft membrane bioreactor. The gas inside the membrane bioreactor is pumped into the gas exchanger 1 under the drive of a peristaltic pump. The gas in the inner space of the gas exchanger 1 and the external gas atmosphere in the outer space of the gas exchanger 1 realize gas exchange across the microporous gas permeable membrane 9 under the action of the partial pressure difference. The high oxygen partial pressure O ₂ outside the gas exchanger 1 enters the gas exchanger 1, and the high carbon dioxide partial pressure CO _{2 in} the gas exchanger 1 is dispersed outside the gas exchanger 1. A gas pressure regulator 4 may also be disposed on the air conduit 3 between the gas exchanger 1 and the gas outlet tube 13. The gas pressure regulator 4 can adjust the inner diameter of the air guiding tube 3 to adjust the bulging state and internal pressure of the soft membrane bioreactor. The shaker, soft membrane bioreactor and gas exchanger can be placed in a carbon dioxide incubator or a three gas incubator. The gas control system of the incubator can be used to accurately control and maintain the temperature, humidity, pressure and composition of the gas environment in the incubator. Further, precise exchange of oxygen and carbon dioxide components in the bioreactor is achieved by gas exchange of the gas exchanger 1.

摇床16根据其摇动的方式，可分为平面轨道摇床、三维摇床和跷跷板摇床。可以根据培养的细胞的种类、生物反应器的结构、混合效果要求和剪切力要求，选择合适的摇床。对于微生物培养而言，通常需要将细胞培养器置于普通恒温摇床。而当进行动物细胞培养时，则需将细胞培养器置于二氧化碳培养箱或三气培养箱。The shaker 16 can be divided into a plane track shaker, a three-dimensional shaker and a seesaw shaker according to the manner in which it is shaken. A suitable shaker can be selected depending on the type of cells to be cultured, the structure of the bioreactor, the mixing effect requirements, and the shearing force requirements. For microbial culture, it is often necessary to place the cell culture incubator on a conventional constant temperature shaker. When performing animal cell culture, the cell culture device is placed in a carbon dioxide incubator or a three-gas incubator.

在一些实施例中，当需要大量和更高效的气体交换时，可采用三通或多通接头通过导气管3将两个或更多个气体交换器1串联或并联，以增大气体交换面积，从而增加气体交换效率。在一些实施例中，当需要增加细胞培养规模时，可采用三通或多通接头通过导气管3将两个或更多个生物反应器串联或并联。In some embodiments, when a large and more efficient gas exchange is required, two or more gas exchangers 1 may be connected in series or in parallel through the air duct 3 using a three-way or multi-way joint to increase the gas exchange area. , thereby increasing gas exchange efficiency. In some embodiments, when it is desired to increase the cell culture scale, two or more bioreactors may be connected in series or in parallel through the airway tube 3 using a three-way or multi-pass joint.

图13为本发明的生物反应器的又一实施例的结构示意图。与图12示出的示例性实施例的结构的不同之处在于，本实施例中的软膜生物反应器的进气管12和出气管13一体地设置在软膜生物反应器的边缘上。例如，软膜生物反应器可以是通过热压两片薄膜而制成的平面软膜波浪生物反应器20。进气管12和出气管13设置在两片薄膜的融合边缘处。进气管12和出气管13可以彼此相邻地设置在生物反应器20上。生物反应器20还可以包括液体进出管23，用于向生物反应器20内注入液体材料和/或生物材料，以及从生物反应器20内取出液体材料和/或生物材料。Figure 13 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention. The difference from the structure of the exemplary embodiment shown in Fig. 12 is that the intake pipe 12 and the outlet pipe 13 of the soft membrane bioreactor in the present embodiment are integrally provided on the edge of the soft membrane bioreactor. For example, the soft membrane bioreactor can be a planar soft membrane wave bioreactor 20 made by hot pressing two sheets of film. The intake pipe 12 and the air outlet pipe 13 are disposed at the fusion edges of the two sheets of film. The intake pipe 12 and the outlet pipe 13 may be disposed adjacent to each other on the bioreactor 20. The bioreactor 20 may also include a liquid inlet and outlet tube 23 for injecting liquid material and/or biological material into the bioreactor 20 and withdrawing liquid material and/or biological material from the bioreactor 20.

图14为本发明的生物反应器的使用的示例性实施例的使用示意图。可以将软膜生物反应器20用固定夹14固定，并通过L形支架27倾斜地置于摇床平台15上。这样的结构可以防培养液在摇床的摇动过程中进入出气管13。在一些实施例中，软膜生物反应器20可以是医疗领域广泛应用的输液袋。可以将本发明的活性通气组件连接至输液袋，从而形成通气式软膜生物反应器。输液袋是普遍应用的医疗用品，具有无毒无害、无致热源、密封好、无渗漏，无菌等优点。与本发明的活性通气组件组合使用，可用于悬浮培养。此外，也可以使用与输液袋结构类似的软膜袋，如输血袋和尿袋等。Figure 14 is a schematic illustration of the use of an exemplary embodiment of the use of a bioreactor of the present invention. The membrane bioreactor 20 can be secured with a retaining clip 14 and placed obliquely on the shaker platform 15 by an L-shaped bracket 27. Such a structure prevents the culture liquid from entering the gas outlet pipe 13 during the shaking of the shaker. In some embodiments, the soft membrane bioreactor 20 can be an infusion bag that is widely used in the medical field. The active ventilating assembly of the present invention can be coupled to an infusion bag to form a vented membrane bioreactor. The infusion bag is a commonly used medical product, which has the advantages of non-toxic and harmless, no heat source, good sealing, no leakage, and sterility. Used in combination with the active ventilating assembly of the present invention, it can be used for suspension culture. In addition, soft film bags similar in structure to the infusion bag, such as blood transfusion bags and urine bags, can also be used.

图15为本发明的生物反应器的又一实施例的结构示意图。该生物反应器可以是气升式生物反应器。本实施例的软膜生物反应器可以由两片软膜结构热压形成，并形成融合圈32。在管口盖11上设置有进气管12和出气管13。在软膜生物反应器外部，可以在进气管12上通过三通接头21连接有液体进出管23。在软膜生物反应器内部，在进气管12上可以连接有曝气管24。该曝气管24上设置有多个微孔。通过进气管12输入的气体可以通过曝气管24上的微孔排出。曝气管24可以延伸到生物反应器的底部。通过蠕动泵泵送至进气管12的气体进入曝气管24，通过微孔喷出微气泡。微气泡在液体内上升。含微气泡的液体密度较低从而上升，导致两侧的高密度液体运动，因此在液体中形成液体的上下循环混合，并实现充分的气体交换。因此，本实施例中的软膜生物反应器不需要摇床的摇动，即可实现液体上下循环以及气体的充分交换。Figure 15 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention. The bioreactor can be an airlift bioreactor. The soft membrane bioreactor of this embodiment can be formed by hot pressing of two sheets of soft film structure and form a fusion ring 32. An intake pipe 12 and an air outlet pipe 13 are provided on the nozzle cover 11. Outside the membrane bioreactor, a liquid inlet and outlet pipe 23 can be connected to the intake pipe 12 via a three-way joint 21. Inside the soft membrane bioreactor, an aeration tube 24 can be connected to the intake pipe 12. The aeration tube 24 is provided with a plurality of micropores. The gas input through the intake pipe 12 can be discharged through the micro holes in the aeration pipe 24. The aeration tube 24 can extend to the bottom of the bioreactor. The gas pumped to the intake pipe 12 by the peristaltic pump enters the aeration tube 24, and microbubbles are ejected through the micropores. The microbubbles rise in the liquid. The liquid containing microbubbles has a lower density and rises, resulting in high-density liquid movement on both sides, thus forming a liquid up-and-down cycle in the liquid and achieving sufficient gas exchange. Therefore, the soft membrane bioreactor of the present embodiment can achieve liquid up and down circulation and full exchange of gas without shaking of the shaker.

图16为本发明的生物反应器的又一实施例的结构示意图。生物反应器可以是三维软膜生物反应器。三维软膜反应器可以通过将两片软膜结构热压在一起而制成。例如，可以利用热塑成型工艺，配合模具制造该三维软膜反应器。在两片软膜相互热熔在一起的部分形成融合圈32。两片软膜中的其中一片具有大于另一片的表面积。例如，在融合圈32所围成区域中，两片软膜中的其中一片的表面积大于另一片的表面积的5％以上，从而在向三维软膜生物反应器中注入液体后，三维软膜生物反应器呈现三维的构造。在示例性实施例中，三维软膜生物反应器可以是三维软膜波浪生物反应器25，其上层软膜为平面状的软膜，而其下层软膜为半球状的三维软膜。在上层软膜上，设置有管口盖11。在一些实例中，可以提供与三维软膜波浪生物反应器25的三维构型相符合的三维硬片壳托26，从而制支撑该三维软膜波浪生物反应器25。三维硬片壳托26可以利用与制造三维软膜波浪生物反应器25相同的模具，由硬片材料热塑成型。该示例性实施例的三维软膜生物反应器的结构类似于硬质的倒圆锥形或半球形摇瓶。因此，可以采用平面回旋摇床对该三维软膜生物反应器进行摇动。Figure 16 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention. The bioreactor can be a three dimensional soft membrane bioreactor. A three-dimensional soft membrane reactor can be made by thermally pressing two soft membrane structures together. For example, the three-dimensional soft membrane reactor can be fabricated using a thermoplastic molding process in conjunction with a mold. A fusion ring 32 is formed in a portion where the two soft films are thermally fused together. One of the two sheets of soft film has a surface area greater than the other sheet. For example, in the region enclosed by the fusion ring 32, the surface area of one of the two soft films is greater than 5% of the surface area of the other film, so that after injecting the liquid into the three-dimensional soft membrane bioreactor, the three-dimensional soft film organism The reactor presents a three-dimensional construction. In an exemplary embodiment, the three-dimensional soft membrane bioreactor may be a three-dimensional soft membrane wave bioreactor 25, the upper soft membrane being a planar soft membrane, and the lower soft membrane being a hemispherical three-dimensional soft membrane. On the upper soft film, a nozzle cover 11 is provided. In some examples, a three-dimensional hard-shell carrier 26 that conforms to the three-dimensional configuration of the three-dimensional soft-film wave bioreactor 25 can be provided to support the three-dimensional soft-film wave bioreactor 25. The three-dimensional hard shell holder 26 can be thermoformed from the hard sheet material using the same mold as the three-dimensional soft film wave bioreactor 25. The structure of the three-dimensional soft membrane bioreactor of this exemplary embodiment is similar to a rigid inverted conical or hemispherical shake flask. Therefore, the three-dimensional soft membrane bioreactor can be shaken using a planar gyro shaker.

图17为本发明的生物反应器的又一实施例的结构示意图。本实施例的生物反应器可以通过将两片软膜结构热压在一起而制成。例如，可以利用热塑成型工艺，配合模具制造该三维软膜反应器。在本实施例中两片软膜均具有三维构型，从而构成双面三维软膜波浪生物反应器35。进气管12和出气管13以及液体进出管23可以一体地设置在融合圈32上。在一些实例中，可以提供与双面三维软膜反应器25的三维构型相符合的三维硬片壳托26。例如，在双面三维软膜反应器25的下方提供三维硬片壳托26，从而支撑该双面三维软膜反应器25。三维硬片壳托26可以利用与制造双面三维软膜反应器25相同的模具，由硬片材料热塑成型。可以将三维硬片壳托26放置在L形支架上，使得双面三维软膜波浪生物反应器25倾置地放置在在摇床平台上，从而放置双面三维软膜反应器25内的液体进入出气管13。Figure 17 is a schematic view showing the structure of still another embodiment of the bioreactor of the present invention. The bioreactor of this embodiment can be made by thermally pressing two sheets of the soft film structure together. For example, the three-dimensional soft membrane reactor can be fabricated using a thermoplastic molding process in conjunction with a mold. In the present embodiment, both of the soft films have a three-dimensional configuration, thereby constituting a double-sided three-dimensional soft film wave bioreactor 35. The intake pipe 12 and the air outlet pipe 13 and the liquid inlet and outlet pipe 23 may be integrally provided on the fusion ring 32. In some examples, a three-dimensional hard-shell carrier 26 that conforms to the three-dimensional configuration of the double-sided three-dimensional soft membrane reactor 25 can be provided. For example, a three-dimensional hard sheet carrier 26 is provided under the double-sided three-dimensional soft membrane reactor 25 to support the double-sided three-dimensional soft membrane reactor 25. The three-dimensional hard shell holder 26 can be thermoformed from the hard sheet material using the same mold as the double-sided three-dimensional soft membrane reactor 25. The three-dimensional hard shell holder 26 can be placed on the L-shaped bracket such that the double-sided three-dimensional soft-film wave bioreactor 25 is placed on the shaker platform in a tilted manner, thereby placing the liquid in the double-sided three-dimensional soft membrane reactor 25 into the chamber. Outlet pipe 13.

本发明的活性通气组件可以与各种不同的生物反应器相配合。生物反应器并不限于上述示例性实施例中列举的种类。例如，生物反应器可以是摇瓶生物反应器，包括锥形瓶和锥底瓶。生物反应器也可以是搅拌罐，包括磁力驱动的搅拌罐和机械传动的搅拌罐。本领域技术人员可以理解，尽管在上述示例性实施例中利用生物反应器进行描述，但本发明的活性通气组件同样适用于细胞培养器。The active venting assembly of the present invention can be mated with a variety of different bioreactors. The bioreactor is not limited to the species listed in the above exemplary embodiments. For example, the bioreactor can be a shake flask bioreactor, including a conical flask and a cone bottom bottle. The bioreactor can also be a stirred tank, including a magnetically driven stirred tank and a mechanically driven stirred tank. Those skilled in the art will appreciate that the active venting assembly of the present invention is equally applicable to cell culture vessels, although described using bioreactors in the above exemplary embodiments.

图18为本发明的细胞培养器的示例性实施例的结构示意图。本实施例的细胞培养器可以是单层细胞培养瓶28。本发明的活性通气组件的接口装置11(例如，管口盖)可以耦接到单层细胞培养瓶28的管口。管口盖11上可以贯通地设置有进气管12和出气管13。在一些实例中，进气管12和出气管13在管口盖内的延伸长度可以不同。例如，进气管12在管口盖内延伸的深度可以大于出气管13在管口盖内延伸的长度。活性通气组件的蠕动泵泵管2可以卡固于蠕动泵泵头6的卡槽内。蠕动泵泵头6装配在蠕动泵驱动器上。在一些实施例中，在气体交换器1与细胞培养瓶28的出气管13之间的导气管3上，可以设置有气压调节器4。通过气压调节器4调节导气管3的内径的大小，从而调节细胞培养瓶28内的气压，从而提供高压培养环境。Figure 18 is a schematic view showing the structure of an exemplary embodiment of the cell culture device of the present invention. The cell culture device of this embodiment may be a single layer cell culture flask 28. The interface device 11 (e.g., the nozzle cover) of the active ventilating assembly of the present invention can be coupled to the orifice of the single layer cell culture flask 28. An intake pipe 12 and an air outlet pipe 13 are provided through the nozzle cover 11 so as to be continuous therethrough. In some examples, the length of extension of the intake tube 12 and the outlet tube 13 within the nozzle cover may vary. For example, the depth of the air intake tube 12 extending within the nozzle cover may be greater than the length of the air outlet tube 13 extending within the nozzle cover. The peristaltic pump tube 2 of the active venting assembly can be clamped into the slot of the peristaltic pump head 6. The peristaltic pump head 6 is mounted on a peristaltic pump drive. In some embodiments, a gas pressure regulator 4 may be disposed on the airway tube 3 between the gas exchanger 1 and the outlet tube 13 of the cell culture flask 28. The inner diameter of the airway tube 3 is adjusted by the gas pressure regulator 4 to adjust the air pressure in the cell culture flask 28, thereby providing a high pressure culture environment.

图19为本发明的细胞培养器的又一示例性实施例的结构示意图。本实施例的细胞培养器可以是多层细胞培养器，例如细胞工厂。本发明的活性通气组件可以具有两个接口装置11。该两个接口装置中的一个可以设有进气管12，而该两个接口装置中的另一个可以设有出气管13。进气管12和出气管13分别与多层细胞培养器的进气通道接口和排气通道接口相耦合，从而形成闭合气体循环环路。本实施例的多层细胞培养器可以用于大规模的细胞培养和生物技术产品的生产。Figure 19 is a schematic view showing the structure of still another exemplary embodiment of the cell culture device of the present invention. The cell culture device of this embodiment may be a multi-layer cell culture device such as a cell factory. The active venting assembly of the present invention can have two interface devices 11. One of the two interface devices may be provided with an intake pipe 12, and the other of the two interface devices may be provided with an air outlet pipe 13. Intake tube 12 and outlet tube 13 are coupled to the inlet channel interface and the exhaust channel interface of the multi-layer cell culture, respectively, to form a closed gas circulation loop. The multi-layer cell culture device of this embodiment can be used for large-scale cell culture and production of biotechnological products.

图20为根据本发明的生物反应器和细胞培养器的使用状态示意图。在一些情况下，细胞培养器或生物反应器体积过大，例如，大于培养箱的容积。在一些情况下，蠕动泵或/和摇床的体积和功率过大，导致产热影响培养箱的温控效果。在一些情况下，生物反应器和细胞培养器不宜置于二氧化碳和三气培养箱内的潮湿环境中。在这些情况下，可以仅将活性通气组件的气体交换器放置在二氧化碳培养箱或三气培养箱内，而将其余装置(例如生物反应器、细胞培养器、蠕动泵、摇床等)置于培养箱之外。例如，通过使导气管穿过培养箱室的通透孔、装配孔或培养箱门的密封间隙，实现不同器件的分别放置。如图20所示，可以将包括大型生物反应器25、多层细胞培养器29、具有多个泵头的大型蠕动泵17以及大型恒温摇床31等装置均置于二氧化碳培养箱或三气培养箱之外。Figure 20 is a schematic view showing the state of use of the bioreactor and cell culture device according to the present invention. In some cases, the cell culture vessel or bioreactor is oversized, for example, larger than the volume of the incubator. In some cases, the volume and power of the peristaltic pump or/and the shaker are too large, causing the heat generation to affect the temperature control effect of the incubator. In some cases, bioreactors and cell cultures should not be placed in a humid environment in carbon dioxide and three gas incubators. In these cases, it is possible to place only the gas exchanger of the active venting assembly in a carbon dioxide incubator or a three-gas incubator, while placing the remaining devices (eg bioreactor, cell culture, peristaltic pump, shaker, etc.) Outside the incubator. For example, separate placement of different devices is achieved by passing the airway through the through hole of the incubator chamber, the mounting hole, or the sealing gap of the incubator door. As shown in FIG. 20, a device including a large bioreactor 25, a multi-layer cell culture device 29, a large peristaltic pump 17 having a plurality of pump heads, and a large-scale constant temperature shaker 31 can be placed in a carbon dioxide incubator or a three-gas culture. Outside the box.

在一些实施例中，为了增强气体交换器的气体交换效率，可以将多个气体交换器串联和/或并联使用。例如，通过三通接头或多通接头，可以从一个导气管分枝出多个导气管，从而将两个或多个气体交换器以并联的方式相连接。这样，可以增加气体交换表面积，从而提高气体交换效率。可以使用具有多个泵头的蠕动泵，同时地驱动多个分支的导气管上的蠕动泵泵管。In some embodiments, to enhance the gas exchange efficiency of the gas exchanger, multiple gas exchangers can be used in series and/or in parallel. For example, a plurality of air tubes can be branched from one air duct through a three-way joint or a multi-way joint to connect two or more gas exchangers in parallel. In this way, the gas exchange surface area can be increased, thereby increasing gas exchange efficiency. A peristaltic pump tube having a plurality of pump heads can be used to simultaneously drive a peristaltic pump tube on a plurality of branched air tubes.

在一些实施例中，可以将两个或更多的细胞培养器或生物反应器的进气管和出气管串联或并联，从而增加细胞培养或生物反应的规模。In some embodiments, two or more cell culture or bioreactor inlet and outlet tubes may be connected in series or in parallel to increase the scale of cell culture or biological response.

在一些实施例中，可以将多个生物反应器和/或细胞培养器分别与多个活性通气组件相连接，利用具有多个泵头的蠕动泵同时实现气体输送。如上所述，可以仅将气体输送装置的气体交换器放置在二氧化碳培养箱或三气培养箱内。In some embodiments, multiple bioreactors and/or cell culturers can be separately coupled to a plurality of active venting assemblies, with a peristaltic pump having multiple pump heads simultaneously achieving gas delivery. As described above, it is possible to place only the gas exchanger of the gas delivery device in a carbon dioxide incubator or a three-gas incubator.

在一些实施例中，软膜生物反应器的进气管和出气管以及液体进出管可以设置在软膜的融合边缘处或者上层平面软膜处。在一些实施例中，可以提供与软膜生物反应器上的管口相配合的管口盖，从而实现活性通气组件与软膜反应器的连通。In some embodiments, the inlet and outlet tubes of the membrane bioreactor and the liquid inlet and outlet tubes may be disposed at the fusion edge of the soft membrane or at the upper planar soft membrane. In some embodiments, a nozzle cap that mates with a nozzle on the membrane bioreactor can be provided to effect communication of the reactive venting assembly with the membrane reactor.

在一些实施例中，可以设置气体压力测量装置对生物反应器和细胞培养器用活性通气组件、生物反应器和/或细胞培养器内的气体压力进行测量，并根据所测量的气体压力控制气体驱动装置的操作。例如，如果所测量的气体压力小于预设值，则可以控制增大蠕动泵的转速。气体压力测量装置可以是气体压力传感器。该气体压力传感器可以设置在气压调节器、管线、容器中的一个或多个位置处。气体压力测量装置可以是非接触式的。In some embodiments, a gas pressure measuring device can be provided to measure the gas pressure in the bioreactor and cell culture device with a reactive venting assembly, a bioreactor, and/or a cell culture device, and control the gas drive based on the measured gas pressure. Operation of the device. For example, if the measured gas pressure is less than a preset value, the increase in the rotational speed of the peristaltic pump can be controlled. The gas pressure measuring device may be a gas pressure sensor. The gas pressure sensor can be placed at one or more locations in the gas pressure regulator, line, or vessel. The gas pressure measuring device can be non-contact.

在一些实施例中，可以在生产所述生物反应器和细胞培养器用活性通气组件、生物反应器和/或细胞培养器后，对该生物反应器和细胞培养器用活性通气组件、生物反应器和/或细胞培养器进行消毒，并进行无菌包装，从而保证该生物反应器和细胞培养器用活性通气组件、生物反应器和/或细胞培养器内的无菌状态。所述消毒可以是紫外线消毒、高温消毒、臭氧消毒等等。In some embodiments, the active venting module, bioreactor, and bioreactor can be used for the bioreactor and cell culture device after production of the bioreactor and cell culture device with a reactive venting assembly, bioreactor, and/or cell culture device. / or the cell culture device is sterilized and aseptically packaged to ensure sterility in the bioreactor and cell culture device with the active venting module, bioreactor and/or cell culture device. The sterilization may be ultraviolet disinfection, high temperature sterilization, ozone sterilization, or the like.

本领域技术人员可以理解，申请中以生物反应器为例描述的实施例，同样也适用于细胞培养器。反之亦然。Those skilled in the art will appreciate that the examples described in the application as examples of bioreactors are equally applicable to cell cultures. vice versa.

尽管本文已经示出和描述了本发明的优选实施方式，但是对于本领域技术人员而言容易理解的是，这样的实施方式只是以举例的方式提供的。本发明不应受到说明书内提供的特定示例的限制。虽然已经参考前述说明书对本发明作出了描述，但本文实施方式的描述和说明不应当以限制性的意义来解释。在不偏离本发明的情况下本领域技术人员现在将会想到许多变型、改变和替换。此外，应当理解，本发明的所有方面都不限于本文阐述的，取决于多种条件和变量的特定描绘、配置或相对比例。应当理解，可以在实践本发明时采用本文所描述的本发明实施方式的各种替代方案。因此，设想到本发明还应当涵盖任何这样的替代、修改、变体或等同项。以下权利要求书旨在限定本发明的范围，并且由此涵盖这些权利要求书的范围内的方法和结构及其等同项。While a preferred embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that such embodiments are provided by way of example only. The invention should not be limited by the specific examples provided in the specification. The description and description of the embodiments herein should be construed in a non-limiting sense, Many modifications, changes and substitutions will now occur to those skilled in the art without departing from the invention. In addition, it should be understood that all aspects of the invention are not limited to the particular descriptions, configurations, or relative proportions of the various conditions and variables. It will be appreciated that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. Therefore, it is contemplated that the invention is also intended to cover any such alternatives, modifications, variations or equivalents. The scope of the invention is intended to be limited only by the scope of the appended claims.

Claims

一种生物反应器和细胞培养器用活性通气组件，包括：An active venting assembly for a bioreactor and a cell culture, comprising:

一个或多个气体交换器，该一个或多个气体交换器中的每一个具有内部空间，并配置为(1)在所述内部空间和所述内部空间之外的外部空间之间进行气体交换，和(2)在进行所述气体交换时阻挡细菌进入所述内部空间；以及One or more gas exchangers, each of the one or more gas exchangers having an internal space and configured to (1) exchange gas between the internal space and an external space outside the internal space And (2) blocking bacteria from entering the interior space during the gas exchange;

管线，该管线在一个或多个容器和所述一个或多个气体交换器之间气密地耦合，从而形成气体流动回路，其中所述容器用于生物发酵或细胞培养，a line that is hermetically coupled between one or more vessels and the one or more gas exchangers to form a gas flow loop, wherein the vessel is for biological fermentation or cell culture,

其中所述管线的至少一部分配置为适于由蠕动泵头驱动，使得气体在所述气体流动回路中沿着预设气体流动方向流动，其中所述气体沿着所述预设气体流动方向依次经过所述蠕动泵头、所述容器、所述一个或多个气体交换器内的气流通道。Wherein at least a portion of the line is configured to be adapted to be driven by a peristaltic pump head such that gas flows in the gas flow circuit along a predetermined gas flow direction, wherein the gas passes sequentially along the predetermined gas flow direction The peristaltic pump head, the vessel, and the gas flow passage within the one or more gas exchangers.
如权利要求1所述的活性通气组件，还包括一个或多个接口装置，该一个或多个接口装置配置为分别与所述一个或多个容器气密地耦合，其中所述接口装置与所述管线气密地耦合。The active vent assembly of claim 1 further comprising one or more interface devices configured to be hermetically coupled to said one or more containers, respectively, wherein said interface device is The pipeline is hermetically coupled.
如权利要求2所述的活性通气组件，其中所述接口装置还包括允许生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器的开口。The active ventilating assembly of claim 2 wherein said interface means further comprises an opening for allowing material and/or product of biological fermentation or cell culture to enter and/or remove said container.
如权利要求3所述的活性通气组件，其中所述开口在未进行所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器期间保持气密封闭。The reactive ventilating assembly of claim 3 wherein said opening remains hermetically sealed during entry and/or removal of said material and/or product from said biological fermentation or cell culture.
如权利要求2所述的活性通气组件，其中所述接口装置包括延伸进入所述容器内部的进气管和出气管，所述进气管和出气管分别与所述管线气密地耦合，并且其中所述进气管延伸进入所述容器内部的长度与所述出气管延伸进入所述容器内部的长度不同。The active vent assembly of claim 2 wherein said interface means includes an intake tube and an air outlet tube extending into the interior of said container, said intake and outlet tubes being hermetically coupled to said line, respectively, and wherein The length of the inlet pipe extending into the interior of the vessel is different than the length of the outlet pipe extending into the interior of the vessel.
如权利要求5所述的活性通气组件，其中所述进气管延伸进入所述容器内部的长度大于所述出气管延伸进入所述容器内部的长度。The active vent assembly of claim 5 wherein the length of the inlet tube extending into the interior of the container is greater than the length of the outlet tube extending into the interior of the container.
如权利要求6所述的活性通气组件，其中所述进气管延伸进入所述容器内部的部分包括柔性管，该柔性管上设置有一个或多个通孔，以允许气体从所述通孔排出。The active vent assembly of claim 6 wherein said portion of said inlet tube extending into said interior of said container comprises a flexible tube having one or more through holes therein for allowing gas to escape from said through opening .
如权利要求1所述的活性通气组件，其中所述管线直接与所述容器气密地耦合，从而形成所述气体流动回路。The reactive vent assembly of claim 1 wherein said line is hermetically coupled to said vessel to form said gas flow circuit.
如权利要求1所述的活性通气组件，其中所述一个或多个气体交换器中的至少一个包括一个或多个膜，所述膜上的孔的孔径被配置为允许所述气体交换并阻止细菌通过。The reactive vent assembly of claim 1 wherein at least one of said one or more gas exchangers comprises one or more membranes, the pores of said membrane having an aperture configured to allow said gas to be exchanged and blocked The bacteria passed.
如权利要求9所述的活性通气组件，其中所述一个或多个气体交换器中的所述至少一个具有框架，并且其中所述一个或多个膜覆盖所述框架的至少一部分。The reactive vent assembly of claim 9, wherein the at least one of the one or more gas exchangers has a frame, and wherein the one or more membranes cover at least a portion of the frame.
如权利要求9所述的活性通气组件，其中所述一个或多个气体交换器中的所述至少一个还包括设置在所述膜之外的至少一个保护网孔片。The reactive vent assembly of claim 9 wherein said at least one of said one or more gas exchangers further comprises at least one protective mesh orifice disposed outside said membrane.
如权利要求1所述的活性通气组件，其中所述一个或多个气体交换器包括多个气体交换器，该多个气体交换器通过所述管线彼此并联或串联。The reactive vent assembly of claim 1 wherein said one or more gas exchangers comprise a plurality of gas exchangers that are connected in parallel or in series with one another via said lines.
如权利要求1所述的活性通气组件，其中所述一个或多个气体交换器中的至少一个具有气体入口和气体出口，其中在所述气体入口和气体出口之间限定气流通道，该气体通道的方向与所述预设气体流动方向一致，并且其中所述气体入口和所述气体出口分别与所述管线气密地耦合。The reactive vent assembly of claim 1 wherein at least one of said one or more gas exchangers has a gas inlet and a gas outlet, wherein an air flow passage is defined between said gas inlet and said gas outlet, said gas passage The direction is coincident with the predetermined gas flow direction, and wherein the gas inlet and the gas outlet are hermetically coupled to the pipeline, respectively.
如权利要求13所述的活性通气组件，其中所述气体入口和所述气体出口彼此相邻地设置。The active vent assembly of claim 13 wherein said gas inlet and said gas outlet are disposed adjacent one another.
如权利要求13所述的活性通气组件，其中所述气体入口和所述气体出口彼此相远离地设置。The active vent assembly of claim 13 wherein said gas inlet and said gas outlet are disposed away from each other.
如权利要求1所述的活性通气组件，其中所述预设气体流动方向与所述气体交换的方向基本上彼此正交。The reactive vent assembly of claim 1 wherein said predetermined gas flow direction and said gas exchange direction are substantially orthogonal to each other.
如权利要求1所述的活性通气组件，其中所述蠕动泵头配置为交替地挤压和释放所述管线的所述至少一部分，从而使得气体在所述气体流动回路中沿着所述预设气体流动方向流动。The reactive vent assembly of claim 1 wherein said peristaltic pump head is configured to alternately compress and release said at least a portion of said line such that gas follows said preset in said gas flow circuit The gas flows in the direction of flow.
如权利要求1所述的活性通气组件，还包括气压调节装置，该气压调节装置设置在所述气体流动回路中的管线外。The active vent assembly of claim 1 further comprising a gas pressure regulating device disposed outside of the line in the gas flow circuit.
如权利要求18所述的活性通气组件，其中所述气压调节装置设置在所述容器和所述一个或多个气体交换器之间。The active ventilating assembly of claim 18 wherein said air pressure adjusting device is disposed between said container and said one or more gas exchangers.
如权利要求18所述的活性通气组件，其中所述气压调节装置配置为改变和/或保持所述管线的管径，从而改变和/或保持所述管线内的气体的压力。The active ventilating assembly of claim 18 wherein said gas pressure regulating device is configured to vary and/or maintain a diameter of said line to thereby change and/or maintain a pressure of gas within said line.
一种活性通气式发酵培养***，包括：An active aerated fermentation culture system comprising:

如权利要求1所述的生物反应器和细胞培养器用活性通气组件；以及The active ventilating assembly for a bioreactor and a cell culture device according to claim 1;

所述一个或多个发酵/培养容器。The one or more fermentation/culture vessels.
如权利要求21所述的***，其中所述容器包括培养瓶、培养袋、细胞工厂、生物发酵罐或生物反应袋中的一种或多种。The system of claim 21 wherein the container comprises one or more of a culture flask, a culture bag, a cell factory, a biological fermentor or a bioreactor bag.
如权利要求21所述的***，还包括一个或多个接口装置，该一个或多个接口装置配置为分别与所述一个或多个容器气密地耦合，其中所述接口装置包括开口，该开口与所述管线气密地耦合。The system of claim 21 further comprising one or more interface devices configured to be hermetically coupled to said one or more containers, respectively, wherein said interface device includes an opening, An opening is hermetically coupled to the line.
如权利要求23所述的***，其中所述接口装置还包括允许所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器的开口。The system of claim 23 wherein said interface means further comprises an opening for allowing said biological fermentation or cell culture material and/or product to enter and/or remove said container.
如权利要求24所述的***，其中所述开口在未进行所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器期间保持气密封闭。The system of claim 24 wherein said opening remains hermetically sealed during entry and/or removal of said material and/or product from said biological fermentation or cell culture into and from said container.
如权利要求23所述的***，其中所述接口装置包括延伸进入所述容器内部的进气管和出气管，所述进气管和出气管分别与所述管线气密地耦合，并且其中所述进气管延伸进入所述容器内部的长度与所述出气管延伸进入所述容器内部的长度不同。A system according to claim 23, wherein said interface means includes an intake pipe and an air outlet pipe extending into the interior of said container, said intake pipe and outlet pipe being hermetically coupled to said line, respectively, and wherein said inlet The length of the trachea extending into the interior of the container is different than the length of the outlet tube extending into the interior of the container.
如权利要求26所述的***，其中所述进气管延伸进入所述容器内部的长度大于所述出气管延伸进入所述容器内部的长度。The system of claim 26 wherein the length of the inlet tube extending into the interior of the container is greater than the length of the outlet tube extending into the interior of the container.
如权利要求27所述的***，其中所述进气管延伸进入所述容器内部的部分包括柔性管，该柔性管上设置有一个或多个通孔，以允许气体从所述通孔排出。The system of claim 27 wherein the portion of the intake tube that extends into the interior of the container comprises a flexible tube having one or more through holes disposed therein to allow gas to escape from the through hole.
如权利要求21所述的***，其中所述所述管线直接与所述容器气密地耦合，从而形成所述气体流动回路。The system of claim 21 wherein said line is hermetically coupled to said vessel to form said gas flow circuit.
如权利要求29所述的***，其中所述容器上还设有允许所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器的开口，所述开口在未进行所述生物发酵或细胞培养的物料和/或产物进入和/或移出所述容器期间保持气密封闭。。A system according to claim 29, wherein said container is further provided with an opening for allowing said biological fermentation or cell culture material and/or product to enter and/or remove said container, said opening not being said The biologically fermented or cell cultured materials and/or products remain hermetically sealed during entry and/or removal from the container. .
如权利要求21所述的***，其中所述一个或多个气体交换器中的至少一个包括一个或多个膜，所述膜上的孔的孔径被配置为允许所述气体交换并阻止细菌通过。The system of claim 21 wherein at least one of said one or more gas exchangers comprises one or more membranes, the pores of said membrane having an aperture configured to allow said gas exchange and to prevent passage of bacteria .
如权利要求31所述的***，其中所述一个或多个气体交换器中的所述至少一个具有框架，并且其中所述一个或多个膜覆盖所述框架的至少一部分。The system of claim 31 wherein said at least one of said one or more gas exchangers has a frame, and wherein said one or more membranes cover at least a portion of said frame.
如权利要求31所述的***，其中所述一个或多个气体交换器中的所述至少一个还包括至少一个设置在所述膜之外保护网孔片。The system of claim 31 wherein said at least one of said one or more gas exchangers further comprises at least one protective mesh orifice disposed outside said membrane.
如权利要求21所述的***，其中所述一个或多个气体交换器包括多个气体交换器，该多个气体交换器通过所述管线彼此并联或串联。The system of claim 21 wherein said one or more gas exchangers comprise a plurality of gas exchangers, said plurality of gas exchangers being connected in parallel or in series with one another via said line.
如权利要求21所述的***，其中所述一个或多个气体交换器中的至少一个具有气体入口和气体出口，其中在所述气体入口和气体出口之间限定气流通道，该气体通道的方向与所述预设气体流动方向一致，并且其中所述气体入口和所述气体出口分别与所述管线气密地耦合。The system of claim 21 wherein at least one of said one or more gas exchangers has a gas inlet and a gas outlet, wherein an air flow passage is defined between said gas inlet and said gas outlet, the direction of said gas passage Consistent with the predetermined gas flow direction, and wherein the gas inlet and the gas outlet are hermetically coupled to the pipeline, respectively.
如权利要求35所述的***，其中所述气体入口和所述气体出口彼此相邻地设置或彼此相远离地设置。The system of claim 35, wherein the gas inlet and the gas outlet are disposed adjacent to each other or away from each other.
如权利要求35所述的***，其中所述预设气体流动方向与所述气体交换的方向基本上彼此正交。The system of claim 35 wherein said predetermined gas flow direction and said gas exchange direction are substantially orthogonal to one another.
如权利要求21所述的***，其中所述蠕动泵头配置为交替地挤压和释放所述管线的所述至少一部分，从而使得气体在所述气体流动回路中沿着所述预设气体流动方向流动。The system of claim 21 wherein said peristaltic pump head is configured to alternately compress and release said at least a portion of said line such that gas flows along said predetermined gas in said gas flow circuit The direction flows.
如权利要求21所述的***，还包括气压调节装置，该气压调节装置设置在所述气体流动回路中的管线外。The system of claim 21 further comprising a gas pressure regulating device disposed outside of the line in said gas flow circuit.
如权利要求39所述的***，其中所述气压调节装置设置在所述容器和所述一个或多个气体交换器之间。The system of claim 39 wherein said air pressure adjusting device is disposed between said container and said one or more gas exchangers.
如权利要求39所述的***，其中所述气压调节装置配置为改变和/或保持所述管线的管径，从而改变和/或保持所述管线内的气体的压力。38. The system of claim 39, wherein the air pressure regulating device is configured to change and/or maintain a diameter of the pipeline to change and/or maintain a pressure of gas within the pipeline.
如权利要求21所述的***，还包括控制器，该控制器与所述气体驱动装置通信地耦合，并配置为根据所述气体流动回路中的压力来调节所述气体驱动装置的操作。The system of claim 21 further comprising a controller communicatively coupled to said gas drive and configured to adjust operation of said gas drive based on pressure in said gas flow circuit.
如权利要求42所述的***，其中所述气体流动回路中的所述压力是在所述容器处测量的。The system of claim 42 wherein said pressure in said gas flow circuit is measured at said vessel.
如权利要求42所述的***，其中所述气体流动回路中的所述压力是采用非接触方式测量的。The system of claim 42 wherein said pressure in said gas flow circuit is measured in a non-contact manner.
如权利要求21所述的***，其中所述一个或多个容器包括多个容器，该多个容器通过所述管线彼此并联或串联。The system of claim 21 wherein said one or more containers comprise a plurality of containers that are connected to each other in parallel or in series by said line.
一种生物反应器和细胞培养器用活性通气组件，其中，所述的活性通气组件包括内部气流通道相连通的至少三部分元件：An active ventilating assembly for a bioreactor and a cell culture device, wherein the active venting assembly comprises at least three components in communication with an internal gas flow passage:

气体交换器，所述气体交换器为具有内部气流通道且串联连通于导气管两管段之间的腔体，所述腔体的至少一个壁面上密封设置有允许气体透过以实现腔体内外气体交换但阻挡细菌透过的微孔透气滤菌膜；a gas exchanger, wherein the gas exchanger is a cavity having an internal gas flow passage and is connected in series between the two pipe sections of the gas pipe, and at least one wall surface of the cavity is sealed to allow gas to permeate to realize gas inside and outside the cavity a microporous permeable membrane that exchanges but blocks the passage of bacteria;

蠕动泵泵管，所述蠕动泵泵管为蠕动泵泵头管卡和挤压驱动其内部气体流动的弹性软管管段；a peristaltic pump tube, which is a peristaltic pump head tube card and an elastic hose tube section that squeezes and drives the internal gas flow thereof;

导气管，所述导气管为连通所述蠕动泵泵管与所述气体交换器之间以及二者分别与待用的生物反应器或细胞培养器的进气管和出气管之间的气体传输管道。An air guiding tube is a gas transmission line connecting the peristaltic pump pump tube and the gas exchanger and the gas inlet and outlet tubes of the bioreactor or cell culture device to be used respectively .
根据权利要求46所述的活性通气组件，其中，所述气体交换器为由两层所述的微孔透气滤菌膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体，所述微孔透气滤菌袋的两端融合有连通管嘴，所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。The active ventilating assembly according to claim 46, wherein said gas exchanger is a microporous permeable filter bag cavity having an internal gas flow passage fused by two layers of said microporous permeable membrane. The two ends of the microporous gas-permeable filter bag are fused with a connecting nozzle, and the connecting nozzle and the air guiding tube are connected by a tight fit or an integrated fusion.
根据权利要求46所述的活性通气组件，其中，所述气体交换器为由两层所述的微孔透气滤菌膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体，所述微孔透气滤菌袋的一端融合有两个连通管嘴，两个连通管嘴之间的两层软膜向袋内融合延伸形成与两个连通管嘴相连通的U形气流通道，所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。The active ventilating assembly according to claim 46, wherein said gas exchanger is a microporous permeable filter bag cavity having an internal gas flow passage fused by two layers of said microporous permeable membrane. One end of the microporous gas permeable filter bag is fused with two communicating nozzles, and two soft films between the two communicating nozzles are fused to the bag to form a U-shaped air flow channel communicating with the two communicating nozzles. The connecting nozzle and the air guiding tube are connected by a tight fit or an integrated fusion.
根据权利要求46所述的活性通气组件，其中，所述气体交换器为设置有透气滤菌膜密封的透气窗的两层阻隔性软膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体，所述微孔透气滤菌袋两端融合有连通管嘴，所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。The active ventilating assembly according to claim 46, wherein said gas exchanger is a microporous permeable filter having an internal gas flow passage fused by a two-layer barrier film provided with a gas permeable membrane sealed gas permeable window. The bag cavity has a communicating nozzle at both ends of the microporous permeable filter bag, and the connecting nozzle and the air guiding tube are connected by a tight fit or an integrated fusion.
根据权利要求46所述的活性通气组件，其中，所述气体交换器为设置有透气滤菌膜密封的透气窗的两层阻隔性软膜融合而成的具有内部气流通道的微孔透气滤菌袋腔体，所述微孔透气滤菌袋的一端融合有两个连通管嘴，两个连通管嘴之间的两层软膜向袋内融合延伸形成与两个连通管嘴相连通的U形气流通道，所述连通管嘴与导气管之间通过紧密配合连接或一体化融合连接。The active ventilating assembly according to claim 46, wherein said gas exchanger is a microporous permeable filter having an internal gas flow passage fused by a two-layer barrier film provided with a gas permeable membrane sealed gas permeable window. a bag cavity, one end of the microporous permeable bag is fused with two communicating nozzles, and two soft films between the two communicating nozzles are fused to the bag to form a U connected to the two communicating nozzles The air flow channel is connected to the air pipe by a tight fit connection or an integrated fusion connection.
根据权利要求46所述的活性通气组件，其中，所述气体交换器为两端带连接管嘴的硬质材料的支撑框架上密封融合有所述微孔透气滤菌膜而成的硬质骨架腔体，所述连通管嘴与导气管之间通过紧密配合连接。The active ventilating assembly according to claim 46, wherein said gas exchanger is a rigid frame formed by sealing a microporous permeable membrane on a support frame of a hard material having a connecting nozzle at both ends. a cavity, the communication nozzle and the air pipe are connected by a close fit.
根据权利要求47至51中任一项所述的活性通气组件，其中，所述微孔透气滤菌膜的外面附设有带通气孔网起支持保护微孔透气滤菌膜作用的网孔片。The active ventilating assembly according to any one of claims 47 to 51, wherein a mesh sheet having a vent mesh to support the microporous permeable membrane is attached to the outside of the microporous permeable membrane.
根据权利要求46所述的活性通气组件，其中，所述的导气管通过三通接头或多通接头并联或串联连通两个或以上气体交换器以增加气体交换效率，或并联或串联连通两个或以上的生物反应器或细胞培养器以增加培养规模。The active vent assembly of claim 46, wherein said air conduits connect two or more gas exchangers in parallel or in series via a three-way joint or a multi-way joint to increase gas exchange efficiency, or to connect two in parallel or in series. Or a bioreactor or cell culture incubator to increase the size of the culture.
根据权利要求46所述的活性通气组件，其中，所述的导气管在气体交换器与所述生物反应器或细胞培养器的出气管之间的管段上设置有通过调节管径大小而调节所述生物反应器或细胞培养器内部气压的气压调节器。The active ventilating assembly according to claim 46, wherein said air guiding tube is disposed on a pipe section between the gas exchanger and the gas pipe of said bioreactor or cell culture device by adjusting the size of the pipe diameter A gas pressure regulator for the internal pressure of a bioreactor or cell culture device.
一种活性通气式生物反应器，其中，所述的活性通气式生物反应器配置有权利要求46至54中任一项所述的活性通气组件；所述的生物反应器为波浪式生物反应器、气升式生物反应器、摇瓶生物反应器或搅拌式生物反应器，所述生物反应器上设置有供气体进出的进气管和出气管，所述活性通气组件的导气管与所述生物反应器的进气管和出气管相连通形成气流通道闭合环路。A reactive aerated bioreactor, wherein the active aerated bioreactor is configured with the active venting assembly of any one of claims 46 to 54; the bioreactor is a wave bioreactor An airlift bioreactor, a shake flask bioreactor or a stirred bioreactor, the bioreactor being provided with an intake pipe and an outlet pipe for gas in and out, an air duct of the active ventilation assembly and the living organism The intake and exhaust pipes of the reactor are connected to form a closed loop of the gas flow passage.
根据权利要求55所述的活性通气式生物反应器，其中，所述生物反应器为软膜生物反应器，所述软膜生物反应器为由2层软膜融合而成的平面软膜生物反应器，或三维软膜生物反应器，所述三维软膜生物反应器为其融合圈内的2层软膜中至少1层软膜的表面积大于融合圈所围成的平面面积5％以上。The aerobic bioreactor according to claim 55, wherein the bioreactor is a soft membrane bioreactor, and the soft membrane bioreactor is a planar soft membrane bioreactor formed by two layers of soft membrane fusion. Or a three-dimensional soft membrane bioreactor, wherein the three-dimensional soft membrane bioreactor has a surface area of at least one soft film of the two soft films in the fusion circle which is larger than a plane area enclosed by the fusion ring by more than 5%.
根据权利要求56所述的活性通气式生物反应器，其中，所述的软膜生物反应器的进气管和出气管贯通融合于所述软膜反应器的两层软膜的融合边，或贯通融合于平面软膜上，或贯通融合于软膜袋的管口所配置的管口盖上，所述贯通融合于管口盖的进气管和出气管分别设置于不同的管口盖或同一管口盖，设置于同一管口盖的进气管和出气管延伸入管口内或反应器内不同的深度。The aerobic bioreactor according to claim 56, wherein the inlet and outlet tubes of the membrane bioreactor pass through a fusion side of the two layers of the soft membrane reactor, or The ventilating tube and the air outlet tube which are fused to the nozzle cover are respectively disposed on different flats or the same tube, and are integrated on the flat soft film or through the nozzle cover disposed on the nozzle of the soft film bag. The flap, the inlet and outlet tubes disposed in the same nozzle cover extend into the nozzle or at different depths within the reactor.
根据权利要求57所述的活性通气式生物反应器，其中，所述软膜生物反应器为通过摇动驱使内部液体形成波浪而实现液体混合和气体交换的波浪式软膜生物反应器。The aerobic bioreactor according to claim 57, wherein said soft membrane bioreactor is a wave type soft membrane bioreactor that achieves liquid mixing and gas exchange by shaking to drive internal liquid to form waves.
根据权利要求58所述的活性通气式生物反应器，其中，所述软膜生物反应器为通过向其内部反应液曝气而实现液体混合和气体交换的气升式软膜生物反应器，所述气升式软膜生物反应器的进气管在袋内连通设置有延伸至反应器底部带细小的曝气孔的曝气管。The aerobic bioreactor according to claim 58, wherein said soft membrane bioreactor is an air-lifting membrane bioreactor for achieving liquid mixing and gas exchange by aeration of a reaction liquid therein. The intake pipe of the airlift type soft membrane bioreactor is connected in the bag with an aeration tube extending to the bottom of the reactor with a small aeration hole.
一种活性通气式细胞培养器，其中，所述的活性通气式细胞培养器配置有权利要求46至54中任一项所述的活性通气组件，所述的细胞培养器为单层细胞培养容器-培养瓶或多层的硬质塑料细胞培养容器，所述单层或多层的硬质塑料细胞培养器具有一个或多个培养器管口，所述培养器管口上配置有管口盖，在所述管口盖上贯通设置有进气管或/和出气管，所述进气管和出气管可设置于同一管口盖或分别设置于不同的管口盖，设置于同一管口盖的进气管和出气管延伸入管口内或反应器内不同的深度，所述活性通气组件的导气管分别与细胞培养器的进气管和出气管通过相连通形成气流通道的闭合环路。A reactive aerated cell culture device, wherein the active aerated cell culture device is configured with the active ventilating assembly of any one of claims 46 to 54, the cell culture device being a single layer cell culture container - a culture bottle or a multi-layered rigid plastic cell culture vessel having one or more incubator nozzles with a spout cap on the mouth of the incubator, An intake pipe or/and an air outlet pipe are disposed through the nozzle cover, and the air inlet pipe and the air outlet pipe may be disposed on the same nozzle cover or respectively disposed on different nozzle covers, and are disposed in the same nozzle cover. The trachea and the outlet tube extend into the nozzle or at different depths within the reactor, and the gas conduits of the active venting assembly are in communication with the inlet and outlet tubes of the cell culture device, respectively, to form a closed loop of the gas flow passage.