WO2009132476A1 - 采样装置，培养液成分检测系统及其检测方法 - Google Patents

采样装置，培养液成分检测系统及其检测方法 Download PDF

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Publication number
WO2009132476A1
WO2009132476A1 PCT/CN2008/000882 CN2008000882W WO2009132476A1 WO 2009132476 A1 WO2009132476 A1 WO 2009132476A1 CN 2008000882 W CN2008000882 W CN 2008000882W WO 2009132476 A1 WO2009132476 A1 WO 2009132476A1
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WIPO (PCT)
Prior art keywords
dialysis tube
path
dialysis
test sample
outflow path
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PCT/CN2008/000882
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English (en)
French (fr)
Inventor
蔡浩原
杨宏伟
孔兵
贺伯特·格里布
卓越
库特·贝腾豪森
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西门子公司
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Application filed by 西门子公司 filed Critical 西门子公司
Priority to PCT/CN2008/000882 priority Critical patent/WO2009132476A1/zh
Publication of WO2009132476A1 publication Critical patent/WO2009132476A1/zh

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4005—Concentrating samples by transferring a selected component through a membrane
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
    • C12M33/14—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus with filters, sieves or membranes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4005—Concentrating samples by transferring a selected component through a membrane
    • G01N2001/4016—Concentrating samples by transferring a selected component through a membrane being a selective membrane, e.g. dialysis or osmosis

Definitions

  • the present invention relates to the field of fermentation, and in particular to a system, method and sampling device for measuring the content of components in a culture solution. Background technique
  • Fig. 1 is a schematic view showing the structure of a system for measuring the content of components in a culture solution in the prior art.
  • the system includes: a fluid device, a sampling device, and a detection device.
  • a sampling device similar to the probe is installed on the fermenter wall containing the culture liquid, and the buffer is injected into the sampling device by the fluid device, and the test component in the culture liquid passes through the semi-permeable property on the sampling device.
  • the structure penetrates into the buffer of the sampling device to form a test sample, and then the formed test sample is sent to a remote detecting device located outside the fermenting tank for detection, and the result information corresponding to the content of the component to be tested is obtained. Further, the result information of the detection device measurement can be converted into corresponding control information by the transducer to control the fermentation process.
  • the test sample waste liquid detected by the detecting device can be discharged into a waste liquid storage device (not shown) in the fluid device.
  • the sampling device in order to obtain a test sample, generally comprises a probe body for mounting on the fermenter wall and supporting the sample and a sample acquisition unit mounted on the probe body, and the sample acquisition unit comprises: a flow for conveying the buffer
  • the dialysis passage that communicates with the flow path for infiltrating the component to be tested in the culture solution into the buffer.
  • 2 is a schematic structural view of a sampling device in the prior art. As shown in Fig. 2, the sampling device comprises: a probe body 1, a flow path 2, 3 and a dialysis passage 4, the dialysis passage 4 comprising a planar dialysis membrane 5, a metal conduit 7 with a notch 6, and a seal for sealing the ends of the passage Blocks 8, 9.
  • pipe 7 is used
  • the planar dialysis membrane 5 is lined on the pipe 7, and covers the port 6, forming a dialysis passage 4 for dialysis by the dialysis membrane 5 at the notch 6.
  • the dialysis passage 4 is immersed in the culture solution, and the buffer enters the dialysis passage 4 through the flow path 2, and the molecules to be tested in the culture solution, such as glucose, lactic acid or minerals, pass through the micropores on the dialysis membrane 5. It enters the dialysis pathway 4 and is fused with the buffer to form a test sample, while macromolecules or microparticles larger than the micropores on the dialysis membrane 5 are isolated outside the dialysis passage 4.
  • the obtained test sample is sent through a flow path 3 to a device located outside the fermenter for detection.
  • the dialysis passage 4 is cleaned by the flow channels 2, 3 to buffer the buffer for the next sampling.
  • the flow path 2 for injecting the buffer solution described above may be referred to as an inflow path
  • the flow path 3 responsible for discharging the buffer solution may be referred to as an outflow path.
  • the present invention provides a sampling device on the one hand and a system and method for measuring the content of a component in a culture solution on the other hand, which not only improves the dialysis efficiency at the time of sampling, but also is relatively easy to clean.
  • a sampling device for a culture solution provided by the present invention comprises: an inflow path for injecting a buffer, an outflow path for deriving a test sample liquid, and a dialysis tube immersed in the culture solution to communicate with the inflow path Between the flow paths.
  • the inflow path is for allowing a buffer to flow into the dialysis tube by itself; the outflow path is for allowing a test sample composed of a buffer and a test substance permeated in the culture solution in the dialysis tube to flow out by itself Used for testing.
  • the dialysis tube is made of a dialysis material, and an inlet end of the dialysis tube is connected to an outlet port of the inflow path, and an outlet end of the dialysis tube is in communication with an inlet end of the outflow path.
  • the inner diameter of the dialysis tube is equal to the inner diameter of the inflow path and the outflow path.
  • the apparatus further comprises: a first connector and a second connector; an inlet end of the dialysis tube is connected to an outlet end of the inflow path through the first connector, the dialysis The outlet end of the tube is connected to the inlet end of the outflow path through the second connector.
  • the inflow path is a tubular body, and the dialysis tube is a U-shaped dialysis tube or a spiral dialysis tube.
  • the number of the dialysis tubes is two or more.
  • the sides of the first connector and the second connector that are connected to the dialysis tube respectively comprise interfaces corresponding to the number of dialysis tubes, each interface being for connection to an outlet end or an inlet end of a dialysis tube, respectively.
  • the apparatus further comprises: a probe body; the inflow path and the outflow path being mounted on the probe body; the spiral dialysis tube being wound around a support frame of the probe body.
  • the dialysis tube is a polysulfone fiber tube.
  • the surface of the dialysis tube has a micropore diameter of less than 0.22 ⁇ m.
  • the culture liquid component detecting system of the present invention comprises: a detecting device for measuring a component to be tested in a test sample; a sampling device; wherein the sampling device includes an inflow path for injecting a buffer, and an exporting The flow path of the test sample liquid and a dialysis tube immersed in the culture liquid are connected between the above-mentioned inflow path and the outflow path.
  • the inflow path is for allowing a buffer to flow into the dialysis tube by itself; the outflow path is for passing a test sample composed of a buffer and a test component infiltrated in the culture solution in the dialysis tube through itself Flows into the detection device for detection.
  • the dialysis tube is made of dialysis material, the inlet of the dialysis tube is connected to the outlet of the inflow path, and the outlet of the dialysis tube is connected to the inlet of the outlet flow path.
  • the sampling device further comprises: a first connector and a second connector; the inlet of the dialysis tube is in communication with the outlet of the inflow path through the first connector, and the outlet of the dialysis tube passes through The second connector is in communication with the inlet of the outflow path.
  • the sampling device further comprises: a probe body mounted on the fermenter wall, a part of the probe body is located in the fermentor, and another part is located outside the fermenter; the inflow path and the outflow path are installed in the On the probe body.
  • the detecting device comprises: a sensor installed on a portion of the probe body outside the fermenter, and communicating with the outflow path for measuring a component to be tested in a test sample transmitted by the flow path And / or content.
  • the culture fluid component detecting system further comprises: a three-way valve between the sensor and the outflow path, the three-way valve being used for measuring a component to be tested and/or At the time of content, the path between the sensor and the outflow path is opened, and the sensor is calibrated to open a path between the sensor and the calibration liquid.
  • the number of the sensors is two or more, and after the sensors are connected in series, the sensors are connected to the outflow path, and each sensor is used to measure one of the test samples transmitted by the flow path. Different components and/or content to be tested.
  • the method for detecting the composition of the culture solution provided by the present invention comprises:
  • the buffer is sent to the dialysis tube in the culture solution through an outlet of the inflow path and an inlet of a dialysis tube;
  • the component to be tested in the culture solution enters the dialysis tube through the micropores on the surface of the dialysis tube, and is fused with the buffer in the dialysis tube to form a test sample liquid;
  • the method further includes: mounting a probe body on which the inflow path, the outflow path, and the dialysis tube are mounted on a fermentor containing a culture solution, a part of the probe body being located in the fermenter The other part is located outside the fermenter, and the sensor in the detecting device is mounted on a portion of the probe body outside the fermenter, and the sensor is connected to the outflow path.
  • the sending of the test sample liquid to the detecting device through the outflow path for detecting in step C includes: sending the test sample liquid to the sensor through the outflow path for detection.
  • the number of the sensors is two or more, and each sensor is used to measure a different component and/or content of the test sample in the flow path.
  • the method further includes: detaching the sensor from the probe body when the culture solution in the fermenter is sterilized, and mounting the sensor on the probe body after the sterilization is completed.
  • the method further includes: injecting the calibration fluid into the sensor through a three-way valve located between the sensor and the outflow path to calibrate the sensor.
  • the dialysis tube made of dialysis material is used as the dialysis passage in the present invention, and the dialysis tube can be dialysis around the dialysis tube, so that the tubular dialysis tube can be larger under the same dialysis passage inner diameter. Improve the dialysis rate.
  • the dialysis tube can be easily replaced, so that The technical solution in the present invention can obtain the required dialysis rate conveniently and quickly.
  • FIG. 2 is a schematic structural view of a sampling device in the prior art
  • FIG. 3 is a schematic structural view of a culture liquid component sampling device according to an embodiment of the present invention
  • FIG. 4 is a partial structural schematic view of a dialysis tube in the sampling device shown in FIG. 3
  • FIG. a partial schematic diagram of the system
  • FIG. 6 is a partial schematic view showing a culture liquid component detecting system according to another embodiment of the present invention
  • FIG. 7 is a partial schematic view showing a culture liquid component detecting system according to still another embodiment of the present invention.
  • An exemplary flow chart An exemplary flow chart. detailed description
  • the dialysis area at the time of dialysis can be increased, and in order to reduce the dead angle at the time of cleaning, the flow path of the delivery buffer and the dialysis passage can be connected as one integral passage, and the present invention is implemented.
  • a dialysis tube made of dialysis material is introduced into the sampling device. It has been found through research and experiment that the dialysis material in the embodiment of the present invention may be polysulfone, and accordingly, the dialysis tube may be a polysulfone fiber tube. In addition, the dialysis material can be other materials that can be used for dialysis.
  • Fig. 3 is a view showing an exemplary configuration of a sampling device for measuring a content of a component in a culture solution in an embodiment of the present invention.
  • the apparatus includes: a probe body 10, an inflow path 20, an outflow path 30, a dialysis tube 40, and a first connector 50 and a second connector 60.
  • the probe body 10 is for mounting on the fermenter wall containing the culture solution, and as shown in FIG. 3, a part of the probe body 10 is located in the fermentor, and the other part is located outside the fermentor.
  • the inflow path 20 and the outflow path 30 are both mounted on the probe body 10, the inlet port of the inflow path 20 is connected to the fluid device, the outlet port of the outflow path 30 is connected to the detecting device, and the test sample waste liquid is detected by the detecting device. It can be discharged into the waste container of the fluid device.
  • the dialysis tube 40 is used for immersing in the culture solution and is made of a dialysis material.
  • the dialysis material may be a polysulfone fiber, because the polysulfone material has high thermal stability and strong acid/alkali resistance.
  • the inlet end of the dialysis tube 40 is connected to the outlet of the inflow path 20 through the first connector 50, and the other end of the dialysis tube is the inlet of the second connector 60 and the outlet path 30 through the first connector 50. Connected to form a complete fluid path with the inflow path 20 and the outflow path 30.
  • the dialysis tube 40 and the inflow path 20 and the outflow path 30 may not be connected through the first connector 50 and the second connector 60, but may be connected by other means, such as by gluing or sealing strips.
  • the way to bundle is connected.
  • the diameter of the micropore on the surface of the dialysis tube 40 can be set according to the size of the component to be tested, and usually, it can be set below 0.22 ⁇ , at which time the molecules of the component to be tested can usually enter the dialysis tube through the micropore.
  • particles such as bacteria are blocked outside the dialysis tube 40, thereby avoiding bacterial contamination.
  • the required dialysis rate and test sample size can be adjusted by changing the inner diameter size and length of the dialysis tube 40.
  • the dialysis rate can be increased by selecting a small inner diameter, such as lmm.
  • the inner diameters of the dialysis tube 40 and the inflow path 20 and the outflow path 30 can be set to the same size, that is, the inner diameters of the three are large, and the cleaning angle is completely eliminated.
  • the dialysis tube 40 can be easily replaced by disassembling the first connector 50 and the second connector 60.
  • the shape of the dialysis tube 40 may be any shape.
  • the dialysis tube 40 has a U shape.
  • the shape of the dialysis tube 40 may also be spiral, as shown in FIG. 4,
  • FIG. 4 is another embodiment of the dialysis tube 40 in the embodiment of the present invention.
  • the dialysis tube 40 itself may not have sufficient elasticity to keep the spiral shape constant, so in order to enhance its ability to retain the shape, As shown in Fig. 4, it is wound around a support frame which can be fixed to the probe body 10 as a part of the probe body.
  • more than two dialysis tubes 40 may be disposed in the embodiment of the present invention, and correspondingly, the first connector 50 and the second connector 60 and the dialysis tube
  • the connected sides of 40 may each include a plurality of interfaces, i.e., interfaces corresponding to the number of dialysis tubes 40, each of which is for connection to a dialysis tube 40, and the side of the first connector 50 that is connected to the inflow path 20 is There may be only one interface, and the side of the second connector 60 connected to the outflow path 30 may have only one interface.
  • the buffer from the inflow path 20 can be simultaneously injected into each of the dialysis tubes 40, and the test samples obtained by the respective dialysis tubes 40 can be simultaneously injected into the flow path 30.
  • the sampling device When the test is performed, the sampling device is mounted on the fermenter wall, and the dialysis tube 40 is immersed in the culture solution.
  • the fluid device injects the buffer into the flow path 20 through the inlet port of the inflow path 20, and further enters through the inflow path 20.
  • a component of the culture solution having a diameter smaller than that of the micropore on the surface of the dialysis tube 40 such as glucose, lactic acid or mineral, penetrates into the dialysis tube 40 through the micropores, and the dialysis tube 40
  • the buffers are fused together to form a test sample solution, and the test sample liquid in the dialysis tube 40 is continuously transferred to the flow path 30 connected to the dialysis tube 40 by external power, and further, the test sample liquid is passed through the outflow.
  • the road 30 is sent to the detecting device for detection to obtain the component and/or content to be tested.
  • the fluid device injects the buffer into the dialysis tube 40 again through the inflow path 20, and cleans the dialysis tube 40, and the washed waste liquid flows out through the outlet path 30, and can be discharged into the waste device of the fluid device. in.
  • the buffer from the inflow path 20 may continue to flow through the dialysis tube 40 and enter the flow path 30, or may remain in the dialysis tube 40 for a certain period of time to allow the test component to be sufficiently infiltrated.
  • the buffer can also continue to flow through the dialysis tube 40 and enter the flow path 30, and an ideal test sample can be obtained at this time.
  • the probe body 10 can also be omitted, that is, the sampling device includes only the inflow path 20, the outflow path 30, and the dialysis tube 40, and the object of the present invention can also be achieved.
  • the detecting device is usually realized by a sensor, and the sensor is usually susceptible to some harsh conditions in the fermentation process, such as the conditions during sterilization.
  • the device is placed far away from the fermenter, which inevitably increases the transmission path of the flow path 30, thereby increasing the transmission time of the test sample and reducing the real-time detection.
  • the sensor in order to improve the real-time detection, is placed in a relatively close to the fermenter.
  • FIG. 5 is a measurement of the content of the component in the culture solution according to the embodiment of the present invention.
  • a partial schematic diagram of the system ie a schematic representation of the position and connection relationship of the test device and the sampling device.
  • the sensor 70 is mounted on a portion of the probe body 10 outside the fermentor, and the sensor 70 is connected to the outlet port of the outflow path 30 for measuring the test sample to be tested in the flow path 30.
  • the component content, the test sample waste liquid detected by the sensor 70 can be discharged into the waste liquid storage device.
  • the sensor 70 in order to avoid the influence of the harsh conditions in the fermentation process on the sensor 70, the sensor 70 may be detached from the probe body 10 during a severe condition such as a sterilization process in the fermentation process, and the sterilization process may be bad. After the conditional process is over, the sensor 70 is mounted on the probe body 10.
  • FIG. 6 is still another partial schematic diagram of the detection system of the culture liquid component in the embodiment of the present invention, that is, the test
  • a plurality of sensors 70 are connected in series with the outflow path 30, that is, a plurality of sensors 70 are connected in series and communicate with the outflow path 30, and each sensor 70 can be used to measure the flow path 30, respectively.
  • the content of a different component to be tested in the transmitted test sample for example: No. 1 sensor 70 is used to measure the content of glucose, No. 2 sensor 70 is used to measure the content of lactic acid, and No. 3 sensor 70 is used to measure the content of ammonium ion. Wait.
  • the branches are connected, and here is no longer - repeat.
  • the calibration liquid needs to pass through the inflow path 20 and the dialysis tube. 40 and the outflow path 30 are injected into the sensor 70 to calibrate the sensor 70. After the calibration is completed, the inflow path 20, the dialysis tube 40, and the outflow path 30 are cleaned by the buffer to prepare for the next detection. When used.
  • a three may be disposed between the sensor 70 and the outflow path 30.
  • valve 80 As shown in FIG. 7, FIG. 7 is a test in the embodiment of the present invention. Yet another partial schematic of the system for the composition and/or content of the broth. Wherein, the three-way valve 80 is used to open the path between the sensor 70 and the outflow path 30 when measuring the component and/or content to be tested, and to calibrate the sensor 70 to open between the sensor 70 and the calibration liquid. path.
  • sampling device and the detection system of the culture liquid component in the embodiment of the present invention have been described in detail above, and the detection method of the culture liquid component in the embodiment of the present invention will be described in detail below.
  • Fig. 8 is an exemplary flow chart showing a method of measuring the content of a component in a culture solution in an embodiment of the present invention. As shown in FIG. 8, the method includes the following steps:
  • the buffer is fed into the dialysis tube in the culture solution through the inflow path.
  • the dialysis tube is made of a dialysis material, and preferably, the dialysis material may be polysulfone.
  • Step 802 the component to be tested in the culture solution enters the dialysis tube through the micropores on the surface of the dialysis tube, and is fused with the buffer in the dialysis tube to form a test sample.
  • Step 803 The test sample is sent to the detecting device through the outflow path for detection, and the content of the component to be tested is obtained.
  • the method of the present embodiment can be applied to a system for measuring the content of components in the culture solution described in the present embodiment.
  • the probe body to which the inflow path, the outflow path and the dialysis tube are mounted may be first mounted on a fermentor containing a culture solution, a part of the probe body being located in the fermentor and another part being located outside the fermenter .
  • a sensor in the detecting device may be mounted on a portion of the probe body located outside the fermentor, and the sensor may be in communication with the outflow path. Then, in step 803, the test sample is sent to the sensor through the outflow path for detection.
  • the senor when the culture solution in the fermenter is sterilized, the sensor can be detached from the probe body, and after the sterilization is completed, the sensor is mounted on the probe body.
  • a three-way valve may be disposed between the sensor and the outflow path, and after every set time, the calibration liquid is injected into the sensor through the three-way valve, and the sensor is calibrated.
  • the dialysis tube can be dialysis around, the same
  • the tubular dialysis tube increases the dialysis rate at the diameter of the dialysis access.
  • a plurality of dialysis tubes can be used, so that the dialysis rate is further improved.
  • the desired dialysis rate can be obtained.
  • the area of the dialysis tube can be increased in a limited space, thereby improving the flexibility of dialysis rate adjustment.
  • the dialysis tube can be easily and quickly replaced, and the hardware structure of the probe body does not need to be changed, the technical solution in the present invention can be more widely applied.
  • the dialysis tube and the flow path can communicate to form a complete passage, and the inner diameter of the dialysis tube can be made consistent with the inner diameter of the flow path, the cleaning dead angle is eliminated during cleaning, and the cleanliness is improved.
  • the length of the outflow path is reduced, that is, the transfer time of the test sample is reduced, thereby improving the real-time detection.

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Description

采样装置， 培养液成分检测系统及其检测方法 技术领域
本发明涉及发酵领域， 特别涉及一种测量培养液中成分含量的系 统、 方法和采样装置。 背景技术
在制药、 能源、 食品、 饮料及环境监测等工业应用中， 发酵处理 是经常会用到的一个关键处理过程， 为了对发酵过程进行合理的控制， 如对发酵产量或发酵质量等进行控制， 通常需要对一些典型的生物参 数进行准确实时的测量， 这些典型的生物参数中通常包括： 培养液中 的成分含量， 如葡萄糖含量、 乳酸含量、 以及矿物质含量等。
图 1 为现有技术中测量培养液中成分含量的系统的结构示意图。 如图 1 所示， 该系统包括： 流体装置、 采样装置和检测装置。 进行检 测时， 将类似于探头的采样装置安装在装有培养液的发酵罐壁上， 由 流体装置将緩沖液注入该采样装置中， 培养液中的待测成分通过采样 装置上的半透性结构渗透进采样装置的緩沖液中， 形成测试样本， 然 后将形成的测试样本送到位于发酵罐外的远端检测装置进行检测， 得 到与待测成分含量对应的结果信息。 进一步地， 可由换能器将检测装 置测量的结果信息转换为对应的控制信息， 以控制发酵过程。 此外， 经检测装置检测后的测试样本废液可排入流体装置中的废液存放器 (图中未示出） 中。
其中， 为了获取测试样本， 采样装置通常包括用于安装在发酵罐 壁并起支撑作用的探头主体和安装在探头主体上的样本获取单元， 且 样本获取单元包括： 用于输送緩冲液的流路和与流路相通的用于使培 养液中待测成分渗透进缓冲液中的透析通路。 图 2 为现有技术中一种 采样装置的结构示意图。 如图 2所示， 该采样装置包括： 探头主体 1、 流路 2、 3和透析通路 4, 该透析通路 4包括平面透析膜 5、 带缺口 6 的金属管道 7和用于密封通路两端的密封块 8、 9。 其中， 管道 7用于
确 认 本 起支撑作用， 将平面透析膜 5衬在管道 7上,. 并覆盖住^口 6, 形成由 缺口 6处的透析膜 5进行透析的透析通路 4。 具体应用时, 将透析通路 4浸入培养液中，緩沖液通过流路 2进入透析通路 4中， 培养液中的待 测成分， 如葡萄糖、 乳酸或矿物质等分子通过透析膜 5 上的微孔进入 透析通路 4 中， 并与緩冲液融合在一起， 构成测试样本， 而大于透析 膜 5上的微孔的大分子或微粒则被隔离在透析通路 4以外。 之后， 得 到的测试样本通过流路 3 送入位于发酵罐外的设备中进行检测。 本次 采样完成后， 通过流路 2、 3输送緩冲液对透析通路 4进行清洗， 以便 进行下次采样。 其中， 为方便描述， 可将上述负责緩沖液注入的流路 2 称为入流路， 将负责緩沖液排出的流路 3称为出流路。
图 2所示采样装置中， 一方面， 由于透析通路 4中只有缺口 6处 对应的面积能进行透析， 因此使得透析率较低； 另一方面， 由于流路 2、, 3位于透析通路 4的内部， 对透析通路 4进行清洗时， 会存在部分难以 清洗干净的死角， 致使对下次采样带来一定的影响。 发明内容
为了解决以上问题， 本发明一方面提供一种采样装置， 另一方面 提供一种测量培养液中成分含量的系统和方法， 不但能提高采样时的 透析效率， 而且比较容易清洗。
本发明所提供的一种培养液的采样装置， 包括： 一个用来注入缓 冲液的入流路、 一个导出测试样本液的出流路， 以及一个浸入培养液 中的透析管连通在上述入流路与出流路之间。
所述入流路用于使緩沖液通过自身流入所述透析管中； 所述出流 路用于使所述透析管中由緩沖液和培养液中渗透的待测成分组成的测 试样本通过自身流出用于检测。 所述透析管由透析材料制成， 且所述 透析管的入口一端与入流路的出端口相连， 透析管的出口端与出流路 的入口端相连通。
较佳地， 所述透析管的内径与所述入流路和出流路的内径相等。 较佳地， 该装置进一步包括： 第一连接器和第二连接器； 所述透 析管的入口端通过所述第一连接器与入流路的出口端相连， 所述透析 管的出口端通过所述第二连接器与出流路的入口端相连。
所述入流路， 所述出流路均为管状物， 所述透析管为 U形透析管 或螺旋形透析管。 所述透析管的个数为两个以上。 所述第一连接器和 第二连接器与所述透析管相连的一侧分别包括与透析管数量一致的接 口， 每个接口分别用于与一个透析管的出口端或入口端相连。
较佳地， 该装置进一步包括： 探头主体； 所述入流路和出流路安 装在所述探头主体上； 所述螺旋形透析管绕在所述探头主体的支持架 上。
较佳地， 所述透析管为聚砜纤维管。 所述透析管表面的微孔直径 小于 0.22μηι。
本发明的培养液成分检测系统， 包括： 一个检测装置， 用于测量 测试样本中的待测成分； 一个采样装置； 其中， 所述采样装置包括一 个用来注入緩冲液的入流路、 一个导出测试样本液的出流路， 以及一 个浸入培养液中的透析管连通在上述入流路与出流路之间。
所述入流路用于使緩冲液通过自身流入所述透析管中； 所述出流 路用于使所述透析管中由缓冲液和培养液中渗透的待测成分组成的测 试样本通过自身流到检测装置中进行检测。 所述透析管由透析材料制 成， 所述透析管的入口与入流路的出口相连， 所述透析管的出口与所 述出流路的入口相连。
较佳地， 所述采样装置进一步包括： 第一连接器和第二连接器； 所述透析管的入口通过所述第一连接器与入流路的出口相连通， 所述 透析管的出口通过所述第二连接器与出流路的入口相连通。
较佳地， 所述采样装置进一步包括： 一个安装在发酵罐壁上探头 主体， 所述探头主体的一部分位于发酵罐内， 另一部分位于发酵罐外； 所述入流路和出流路安装在所述探头主体上。
所述检测装置包括： 传感器， 所述传感器安装在所述探头主体位 于发酵罐外的部分上， 并与所述出流路相连通， 用于测量出流路传送 的测试样本中的待测成分和 /或含量。
较佳地， 该培养液成分检测系统进一步包括： 位于所述传感器与 所述出流路之间的一个三通阀， 所述三通阀用于在测量待测成分和 /或 含量时， 打开所述传感器与所述出流路之间的通路， 在对所述传感器 进行标定时， 打开所述传感器与标定液之间的通路。
所述传感器的个数最好为两个或两个以上， 所述各传感器串联连 接后， 与所述出流路相连通， 各传感器分别用于测量出流路传送的测 试样本中的一种不同待测成分和 /或含量。
本发明所提供的培养液成分的检测方法， 包括：
A、将緩冲液通过一个入流路的出口及一个透析管的入口送入位于 培养液中的所述透析管中；
B、 培养液中的待测成分通过所述透析管表面的微孔进入透析管 内， 与所述透析管内的緩冲液融合在一起， 形成测试样本液；
C>将所述测试样本液通过所述透析管的出口及送入一个出流路的 入口端， 所述出流路将所述的测试样本液送到检测装置进行检测。
较佳地， 步骤 A之前， 进一步包括： 将安装有所述入流路、 出流 路和所述透析管的探头主体安装在盛放培养液的发酵罐上， 所述探头 主体的一部分位于发酵罐内， 另一部分位于发酵罐外， 将所述检测装 置中的传感器安装在所述探头主体位于发酵罐外的部分上， 并使所述 传感器与所述出流路相连通。
步骤 C中所述将测试样本液通过出流路送到检测装置进行检测包 括： 将所述测试样本液通过出流路送给所述传感器进行检测。
较佳地， 所述传感器的个数为两个以上， 各传感器分别用于测量 出流路传送的测试样本液中的一种不同待测成分和 /或含量。
该方法进一步包括： 在对发酵罐中的培养液进行消毒时， 将所述 传感器从所述探头主体上拆卸下来， 并在消毒结束后， 将所述传感器 安装在所述探头主体上。
该方法进一步包括： 将标定液通过位于所述传感器和所述出流路 之间的三通阀注入所述传感器中， 对所述传感器进行标定。
从上述方案可以看出， 本发明中采用了由透析材料制成的透析管 作为透析通路， 而透析管的周围均可以进行透析， 使得在同样的透析 通路内径下， 采用管状透析管可较大的提高透析率。 此外， 由于透析 管的内径和长度可以自由选择， 并且透析管可方便的进行更换， 使得 本发明中的技术方案可以方便快捷的得到所需的透析率。 另外， 由于 所述的入流路、 出流路以及透析管连通成为一个连续的流体路径， 容 易进行彻底的清洗， 不会留下难于清洗的流体路径死角， 因而不会影 响后续采样的准确性。 附图说明
下面将通过参照附图详细描述本发明的示例性实施例， 使本领域 的普通技术人员更清楚本发明的上述及其他特征和优点， 附图中： 图 1为现有技术中培养液成分的检测系统的结构示意图； 图 2为现有技术中一种采样装置的结构示意图；
图 3为本发明实施例中培养液成分采样装置的示例性结构图； 图 4为图 3所示采样装置中透析管的一个局部结构示意图； 图 5 为本发明一个实施例中培养液成分检测系统的一个局部示意 图；
图 6为本发明另一实施例中培养液成分检测系统的局部示意图； 图 7为本发明又一实施例中培养液成分检测系统的局部示意图； 图 8为本发明的培养液成分检测方法的示例性流程图。 具体实施方式
本发明中， 为了提高透析率， 可增大进行透析时的透析面积， 并 为了减少清洗时的死角， 可使输送緩沖液的流路和透析通路连通为一 个整体通路， 为此， 本发明实施例中， 将由透析材料制成的透析管引 入采样装置中。 通过研究及实验发现， 本发明实施例中的透析材料可 以为聚砜， 相应地， 透析管可以为聚砜纤维管。 此外， 透析材料也可 以为其它可以实现透析的材料。
为使本发明的目的、 技术方案及优点更加清楚明白， 以下参照附 图并举实施例， 对本发明进一步详细说明。
图 3为本发明实施例中测量培养液中成分含量时采样装置的示例 性结构图。 如图 3所示， 该装置包括： 探头主体 10、 入流路 20、 出流路 30、 透析管 40以及第一连接器 50和第二连接器 60。 其中， 探头主体 10用于安装在盛放培养液的发酵罐壁上， 且如图 3 所示， 探头主体 10的一部分位于发酵罐内， 另一部分位于发酵罐外。
入流路 20和出流路 30均安装在探头主体 10上， 入流路 20的入 端口与流体装置相连， 出流路 30的出端口与检测装置相连， 并且经检 测装置检测后的测试样本废液可排入流体装置的废液存放器中。
透析管 40用于浸入培养液中， 由透析材料制成， 本实施例中， 透 析材料可以为聚砜纤维， 因为聚砜材料具有较高的热稳定性和较强的 耐酸 /碱性， 可满足发酵系统的消毒要求等， 此外， 透析管 40的入口一 端通过第一连接器 50与入流路 20的出口相连， 透析管的另一端即出口 通过第二连接器 60与出流路 30的入口相连， 从而与入流路 20、 出流路 30构成一个完整的流体通路。 当然， 实际应用时， 透析管 40和入流路 20及出流路 30之间也可以不通过第一连接器 50和第二连接器 60相连， 而通过其它方式相连， 如通过胶粘或密封条捆绑的方式相连。 （ 其中， 该透析管 40表面的微孔直径可根据待测成分的大小进行设 置， 通常情况下， 可设置在 0.22μπι以下， 此时待测成分的分子通常可 以通过该微孔进入到透析管 40中， 而细菌等微粒则被阻隔在透析管 40 之外， 从而避免了细菌的污染。
本实施例中， 可通过改变透析管 40的内径大小和长度， 来对所需 要的透析率和测试样本量进行调整。例如，通过选择小的内径， 如 lmm 等， 可提高透析率。 进一步地， 为了减少清洗时的死角， 可将透析管 40与入流路 20、 出流路 30的内径设置为一样的大小， 即三者的内径大 'J、一致， 从而彻底消除清洗死角。 此外， 本发明实施例中， 在采用第 一连接器 50和第二连接器 60时， 还可通过拆装第一连接器 50和第二连 接器 60， 对透析管 40进行方便的更换。
其中， 透析管 40的形状可以为任意形状。 图 3中， 透析管 40的形状 为 U形。 进一步地， 若为了在有限的空间内增大透析管 40的长度， 则该 透析管 40的形状还可以为螺旋形， 如图 4所示， 图 4为本发明实施例中 透析管 40的又一个结构示意图。 通常情况下， 该透析管 40本身可能不 具有足够的弹性以保持螺旋形不变， 因此为了增强其保持形状的能力， 可如图 4所示， 将其绕在一个支撑架上， 该支撑架可固定在探头主体 10 上， 作为探头主体的一部分。
此外， 为了进一步提高透析效率， 本发明实施例中可设置两个以 上的透析管 40 (图中未示出）， 则相应地， 第一连接器 50和第二连接器 60与所述透析管 40相连的一侧可分别包括多个接口， 即与透析管 40数 量一致的接口， 每个接口分别用于与一个透析管 40相连， 而第一连接 器 50与入流路 20相连的一侧则可只有一个接口， 第二连接器 60与出流 路 30相连的一侧也可只有一个接口。 此时， 来自入流路 20的緩沖液可 同时注入各透析管 40中， 各透析管 40获得的测试样本可同时注入出流 路 30中。
进行检测时， 将该采样装置安装在发酵罐壁上， 使透析管 40浸入 培养液中， 流体装置将緩冲液通过入流路 20的入端口注入入流路 20中， 并进一步通过入流路 20进入透析管 40中， 培养液中直径小于透析管 40 表面微孔的待测成分， 如葡萄糖、 乳酸或矿物质等分子通过所述微孔 渗透进所述透析管 40中， 与透析管 40中的緩冲液融合在一起， 形成测 试样本液， 透析管 40中的测试样本液在外部动力的作用下继续向与透 析管 40连接的出流路 30中传送， 进一步地， 测试样本液通过出流路 30 传送到检测装置中进行检测， 得到待测成分和 /或含量。
检测完毕后， 流体装置将緩沖液再次通过入流路 20注入透析管 40 中， 对透析管 40进行清洗， 清洗后的废液通过出流路 30流出， 并可排 入流体装置的废液存放器中。
上述过程中， 来自入流路 20的緩沖液可持续流经透析管 40后进入 出流路 30中， 也可在注入透析管 40后停留特定的时间， 以使培养液中 的待测成分充分渗透入透析管 40中。 当然， 在透析管 40的透析率较高 的情况下， 緩冲液也可持续流经透析管 40后进入出流路 30， 此时同样 可以得到理想的测试样本。
实际应用中， 探头主体 10也可以省略， 即采样装置只包括入流路 20、 出流路 30和透析管 40， 同样也可实现本发明中的目的。
现有技术中， 检测装置通常由传感器实现， 而传感器由于容易受 发酵过程中的一些恶劣条件， 如消毒时条件所影响， 因此通常将传感 器放置在离发酵罐较远的地方， 这样一来， 势必增加出流路 30的传输 路径， 从而增加了测试样本的传输时间， 降低了检测的实时性。 本实 施例中， 为了提高检测的实时性， 将传感器设置在离发酵罐较近的地 方， 具体实现时， 可如图 5所示， 图 5为本发明实施例中测量培养液中 成分含量的系统的一个局部示意图， 即测试装置和采样装置的位置及 连接关系示意图。 图 5中， 将传感器 70安装在探头主体 10位于发酵罐外 的部分上， 并使传感器 70与出流路 30的出端口相连通， 用于测量出流 路 30传送的测试样本中的待测成分含量， 经传感器 70检测后的测试样 本废液可排入废液存放器中。 本实施例中， 为了避免发酵过程中的恶 劣条件对传感器 70的影响， 可在发酵过程中的消毒过程等恶劣条件过 程中， 将传感器 70从探头主体 10上拆卸下来， 并在消毒过程等恶劣条 件过程结束后， 将传感器 70安装在探头主体 10上。
进一步地， 为了提高测试效率， 本发明实施例中可设置两个以上 的传感器 70, 如图 6所示， 图 6为本发明实施例中培养液成分的检测系 统的又一个局部示意图， 即测试装置和采样装置的位置及连接关系的 又一个示意图。 图 6中， 多个传感器 70通过串联的方式与出流路 30相连 通， 即多个传感器 70通过串联连接后与出流路 30相连通， 则各传感器 70可分别用于测量出流路 30传送的测试样本中的一种不同待测成分的 含量， 例如： 1号传感器 70用于测量葡萄糖的含量， 2号传感器 70用于 测量乳酸的含量， 3号传感器 70用于测量铵离子的含量等。 支相连通， 此处不再——赘述。
由于传感器在使用一段时间后， 可能出现刻度的漂移， 因此需要 利用标定液对传感器进行标定， 根据现有技术中的方法， 每隔设定时 间后， 需将标定液通过入流路 20、 透析管 40以及出流路 30注入传感器 70中， 以对传感器 70进行标定， 在标定完成后， 再利用缓冲液对入流 路 20、 透析管 40以及出流路 30等进行清洗， 以备下次进行检测时使用。
本发明实施例中， 为了避免标定液流经入流路 20、 透析管 40以及 出流路 30时， 对将来的测试样本造成潜在的污染， 可在传感器 70与出 流路 30之间设置一个三通阀 80， 如图 7所示， 图 7为本发明实施例中测 量培养液中成分和 /或含量的系统的又一个局部示意图。 其中， 该三通 阀 80用于在测量待测成分和 /或含量时，打开传感器 70与出流路 30之间 的通路， 在对传感器 70进行标定时， 打开传感器 70与标定液之间的通 路。
以上对本发明实施例中的采样装置及培养液成分的检测系统进行 了详细描述， 下面再对本发明实施例中培养液成分的检测方法进行详 细描述。
图 8为本发明实施例中测量培养液中成分含量的方法的示例性流 程图。 如图 8所示， 该方法包括如下步骤：
步骤 801 , 将緩沖液通过入流路送入位于培养液中的透析管中。 本实施例中， 透析管由透析材料制成， 较佳地， 该透析材料可以 为聚砜。
步骤 802， 培养液中的待测成分通过透析管表面的微孔进入透析管 内， 与所述透析管内的緩沖液融合在一起， 形成测试样本。
步骤 803 , 将所述测试样本通过出流路送到检测装置进行检测， 得 到待测成分的含量。
具体实现时， 本实施例中的方法可应用于本实施例中所描述的测 量培养液中成分含量的系统上。 即可首先将安装有所述入流路、 出流 路和所述透析管的探头主体安装在盛放培养液的发酵罐上， 所述探头 主体的一部分位于发酵罐内， 另一部分位于发酵罐外。 进一步地， 可 将所述检测装置中的传感器安装在所述探头主体位于发酵罐外的部分 上， 并使所述传感器与所述出流路相连通。 则步骤 803中， 将所述测试 样本通过出流路送给所述传感器进行检测。
同样， 在对发酵罐中的培养液进行消毒时， 可将所述传感器从所 述探头主体上拆卸下来， 并在消毒结束后， 将所述传感器安装在所述 探头主体上。
且进一步可在传感器与出流路之间设置一个三通阀， 并每隔设定 时间后， 将标定液通过该三通阀注入所述传感器中， 对所述传感器进 行标定。
本发明实施例中， 由于透析管的周围均可以进行透析， 使得在同 样的透析通路直径下， 管状透析管提高了透析率。 并且进一步地， 透 析管可以采用多个， 使得进一步提高了透析率。
其次， 通过改变透析管的内径大小和长度， 可以得到所需要的透 析率。 并且通过将透析管做成螺旋形， 可以在有限的空间内增大透析 管的面积， 从而提高了透析率调整的灵活性。 此外， 由于透析管能够 方便快捷的更换， 并且无须改变探头主体的硬件结构， 使得本发明中 的技术方案能够得到更广泛的应用。
再次， 由于透析管和流路可连通构成一个完整的通路， 并且透析 管的内径可以和流路的内径取得一致， 使得清洗时消除了清洗死角， 提高了清洁度。
此外， 通过将传感器设置在离发酵罐较近的地方， 从而减少了出 流路的长度， 即降低了测试样本的传送时间， 从而提高了检测的实时 性。
最后， 通过设置多个传感器， 并使多个传感器从同一路测试样本 对不同待测成分进行检测， 从而提高了检测效率。
以上所述仅为本发明的较佳实施例而已， 并非用于限定本发明的 保护范围。 凡在本发明的精神和原则之内， 所作的任何修改、 等同替 换以及改进等， 均应包含在本发明的保护范围之内。

Claims

权 利 要 求 书
1、 一种培养液的采样装置， 包括： 一个用来注入緩沖液的入流路 ( 20 )、 一个导出测试样本液的出流路（ 30 ) 以及一个浸入培养液中的 透析管 （40)连通在上述入流路与出流路之间。
2、 如权利要求 1所述的装置， 其中， 所述透析管 （40) 的内径与 所述入流路（ 20 ) 和出流路 (30) 的内径相等。
3、 如权利要求 1所述的装置， 其中， 该装置进一步包括： 第一连 接器 （50)和第二连接器 （60); 所述透析管 （40) 的入口通过所述第 一连接器 （50) 与入流路（20) 的出口相连通， 所述透析管 （40) 的 出口通过所述第二连接器 （60) 与出流路（30) 的入口相连通。
4、 如权利要求 1所述的装置， 其中， 所述入流路（20) 为一管状 物； 所述出流管 （30) 为一管状物。
5、 如权利要求 1所述的装置， 其中， 所述透析管 （40)为 U形透 析管或螺旋形透析管。
6、 如权利要求 5所述的装置， 其中， 该装置进一步包括： 一个探 头主体 （10);
所述入流路（20) 和出流路（30) 均安装在所述探头主体 （ 10) 上；
所述螺旋形透析管绕在所述探头主体 （ 10) 的支持架上。
7、如权利要求 1至 6中任一项所述的装置，其中，所述透析管（40) 为聚讽纤维管。
8、如权利要求 1至 6中任一项所述的装置，其中，所述透析管（ 40 ) 表面的微孔直径小于 0.22μηι。
9、 一种培养液成分检测系统， 包括： 一个检测装置， 用于测量测 试样本中的待测成分； 一个采样装置； 其中， 所述采样装置包括一个 用来注入緩冲液的入流路 ( 20 )、 一个导出测试样本液的出流路（ 30 ), 以及一个浸入培养液中的透析管 （40)连通在上述入流路与出流路之 间。
10、 如权利要求 9所述的系统， 其中， 所述采样装置进一步包括： 第一连接器（50)和第二连接器 （60); 所述透析管 （40) 的入口通过 所述第一连接器 （50) 与所述入流路（20) 的出 cr.相连通， 所述透析, 管 (40) 的出口通过所述第二连接器 (60) 与所述出流路（30) 的人 口相连通。
11、 如权利要求 9所述的系统， 其中， 所述采样装置进一步包括： 一个安装在发酵罐壁上的探头主体（10)， 所述探头主体（10) 的一部 分位于发酵罐内， 另一部分位于发酵罐外； 所述入流路 （20) 和出流 路（30)安装在所述探头主体 （ 10)上；
所述检测装置包括： 传感器（70), 所述传感器（70)安装在所述 探头主体 （10)位于发酵罐外的部分上， 并与所述出流路（30)相连 通， 用于测量出流路（30)传送的测试样本中的待测成分和 /或含量。
12、如权利要求 11所述的系统， 其特征在于， 该系统进一步包括： 位于所述传感器（70) 与所述出流路 (30)之间的一个三通阀 （80), 所述三通阀 （80)用于在测量待测成分和 /或含量时， 打开所述传感器
(70) 与所述出流路（30)之间的通路， 在对传感器 （70) 进行标定 时， 打开所述传感器 （70) 与标定液之间的通各。
13、 如权利要求 11所述的系统， 其特征在于， 所述传感器 （70) 的个数为两个以上， 所述各传感器 （70)通过串联连接后， 与所述出 流路（30)相连通， 各传感器 （70)分别用于测量出流路 (30)传送 的测试样本中的一种不同待测成分和 /或含量。
14、 一种培养液成分的检测方法， 包括：
A、将緩冲液通过一个入流路的出口端及一个透析管的入口端送入 位于培养液中的所述透析管中；
B、 培养液中的待测成分通过透析管表面的微孔进入所述透析管 内， 与所述透析管内的緩冲液融合在一起， 形成测试样本液；
C、将所述测试样本液通过所述透析管的出口端送入一个出流路的 入口端， 所述出流路将所述的测试样本液送到检测装置进行检测。
PCT/CN2008/000882 2008-04-30 2008-04-30 采样装置，培养液成分检测系统及其检测方法 WO2009132476A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1358994A (zh) * 2000-12-18 2002-07-17 中国科学院化学研究所 传感器型微透析生物活体取样装置
CN1402009A (zh) * 2002-09-27 2003-03-12 江南大学 一种生物反应过程在线检测系统的取样稀释装置

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1358994A (zh) * 2000-12-18 2002-07-17 中国科学院化学研究所 传感器型微透析生物活体取样装置
CN1402009A (zh) * 2002-09-27 2003-03-12 江南大学 一种生物反应过程在线检测系统的取样稀释装置

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