Patent Application
20160264922
The present disclosure relates to a cell management system which manages cells cultured in an automatic culture system installed in a cell culture factory.
In the related art, there have been proposed a management method and a management system which manage culture of cells. In this publication, there is disclosed a management method that uses a cell culture system which is capable of forming stem cells by culturing cells collected from a collection subject, separating and growing the cells to form a stem cell and capable of obtaining cultured cells or cultured tissues. More specifically, if a scheduled shipping date on which cultured cells or cultured tissues are shipped is set from a date on which the cultured cells are used, individual items are automatically calculated in the order of a culture completion time, a subculture implementation time, a growth factor input time, a culture start time, a separating work time, a reception inspection time and a reception time based on a standard culture schedule, thereby specifying schedules of the respective items.
However, the aforementioned management method merely has the purpose of managing a culture plane of collected cells in conformity with a treatment plan, controlling a culture speed of cells under culture in conformity with a patient condition or a surgery schedule and scheduling a shipping date of stem cells or tissues. It is not assumed that a cell ordering party such as a hospital or a pharmaceutical company figures out, in real time, the kind and state of cells cultured at the present stage in a cell culture factory. It is therefore impossible to meet such a need. Furthermore, cells used in treatment need to be cultured in large quantities. However, production management involves difficulties due to different factors such as an error in cell growth rate, disposal of defective cells, trouble of a cell culture device and limitation in cell culture device performance
The present disclosure provides a cell management system which is capable of figuring out, in real time, the kind and state of cells cultured at the present stage in a cell culture factory.
According to one embodiment of the present disclosure, there is provided a cell management system, including: an automatic culture system installed in a cell culture factory, the automatic culture system including an automatic culture device configured to automatically culture cells and a cell management part configured to manage information on a state of the cells being cultured in the automatic culture device; a memory part connected to the automatic culture system so as to make communication therewith and configured to store information on the state of the cells being cultured in the automatic culture device therein; and an external computer installed in a side of a cell ordering party and connected to the memory part so as to make communication therewith, wherein the automatic culture system is configured to send the information on the state of the cells managed by the cell management part to the memory part in real time, and the external computer includes a display part configured to display the information on the state of the cells stored in the memory part thereon and an manipulation part configured to order the cells under culture within the cell culture factory.
The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate embodiments of the present disclosure, and together with the general description given above and the detailed description of the embodiments given below, serve to explain the principles of the present disclosure.
Reference will now be made in detail to various embodiments, examples of which are illustrated in the accompanying drawings. In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. However, it will be apparent to one of ordinary skill in the art that the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, systems, and components have not been described in detail so as not to unnecessarily obscure aspects of the various embodiments.
One embodiment of a cell management system according to the present disclosure will now be described with reference to the drawings.
The cell management system of this embodiment can be used in managing different cells including pluripotent stem cells such as (human) iPS cells, (human) ES cells or the like, chondrocytes such as bone marrow stromal cells (MSC) or the like, dendritic cells, and so forth. In this embodiment, descriptions will be made based on iPS cells. However, it should be noted that this is nothing more than one example. Furthermore, the term “cells” used in this embodiment refers to iPS cells, differentiated cells or both
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Examples of cells cultured in the cell culture factories 100 include autologous cells (isogenic cells) which are collected from a collection subject and returned to the collection subject, and cross-cells (allogeneic cells) which are collected from a collection subject and returned to a person other than the collection subject. In the case of the autologous cells, raw material cells collected from a collection subject are cultured by rewinding the same around iPS cells or cultured by differentiating the same from iPS cells into differentiated cells. It is therefore difficult to meet the need of the cell ordering parties 200 who want to use the cells on the spot or in the near future. On the other hand, in the case of the cross-cells, raw material cells are collected from multiple collection subjects in advance. The raw material cells can be cultured by rewinding the same around iPS cells or can be cultured by differentiating the same from iPS cells into differentiated cells. It is therefore easy to meet the need of the cell ordering parties 200 who want to use the cells on the spot or in the near future. By the way, whether the cross-cells can be transplanted into the body of a patient may be determined depending on, for example, whether the immune type of the patient is the same as the immune type of cells.
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Descriptions will now be made on the device configuration of the automatic culture system 110 according to this embodiment.
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In this embodiment, as described above, an aspect using iPS cells is described. Thus, as illustrated in
The automatic culture devices 20 and 30 of this embodiment include a plurality of (four, in the aspect illustrated in
In this embodiment, in addition to the first airtight container 70, there are employed the second airtight containers 75 which accommodate cells (see
The iPS cell automatic culture device 20 includes a housing 22 illustrated in
The liquid storage supply part 26 described above appropriately supplies a liquid culture medium from an inlet (not shown) into the second airtight container 75, thereby automatically replacing an old liquid culture medium existing within the second airtight container 75 with a new one. Based on the information of the iPS cells acquired, the cell inspection removal part 25 selectively peels off defective iPS cells from an ECM (Extracellular Matrix) coated on a surface of the film of the second airtight container 75. Thereafter, the liquid storage supply part 26 supplies a liquid culture medium from the inlet into the second airtight container 75, whereby floating defective iPS cells are pushed out from the second airtight container 75 through an outlet (not shown). As the method of selectively peeling off the iPS cells existing within the second airtight container 75, a method of irradiating ultrasonic waves or light on the iPS cells or a method of applying a physical force from outside of the second airtight container 75 may be used.
Furthermore, the liquid storage supply part 26 appropriately supplies a proteolytic enzyme from the inlet into the second airtight container 75, thereby peeling off the iPS cells from the ECM coated on the surface of the film of the second airtight container 75. Thereafter, the liquid storage supply part 26 supplies a liquid culture medium from the inlet into the second airtight container 75, whereby floating iPS cells are pushed out from the second airtight container 75 through the outlet. The iPS cells thus pushed out are diluted into a suspension and are then accommodated (seeded) within a plurality of other second airtight containers 75. In this way, the iPS cell automatic culture device 20 automatically performs the subculture of the iPS cells.
An internal temperature of the incubator part 27 is adjusted so that the internal temperature becomes, for example, about 37 degrees C. Furthermore, the gas concentration within the incubator part 27 is adjusted by appropriately adding CO2 to the air. If necessary, the humidity may be adjusted by the incubator part 27 so as to become about 100%.
The differentiated cell automatic culture device 30 includes a housing 32 illustrated in
The liquid storage supply part 36 described above appropriately supplies a liquid culture medium from the inlet into the second airtight container 75, thereby automatically replacing an old liquid culture medium existing within the second airtight container 75 with a new one. Based on the information of the differentiated cells acquired, the cell inspection removal part 35 selectively peels off defective differentiated cells from an ECM (Extracellular Matrix) coated on the surface of the film of the second airtight container 75. Thereafter, the liquid storage supply part 26 supplies a liquid culture medium from the inlet into the second airtight container 75, whereby floating defective differentiated cells are pushed out from the second airtight container 75 through the outlet. When inducing differentiation, the liquid storage supply part 36 of the differentiated cell automatic culture device 30 may supply a liquid culture medium including a differentiation-inducing factor.
Furthermore, the liquid storage supply part 36 appropriately supplies a proteolytic enzyme from the inlet into the second airtight container 75, thereby peeling off the differentiated cells from the ECM coated on the surface of the film of the second airtight container 75. Thereafter, the liquid storage supply part 26 supplies a liquid culture medium from the inlet into the second airtight container 75, whereby floating differentiated cells are pushed out from the second airtight container 75 through the outlet. The differentiated cells thus pushed out are diluted into a suspension and are then accommodated (seeded) within a plurality of other second airtight containers 75. In this way, the differentiated cell automatic culture device 30 automatically performs the subculture of the differentiated cells.
An internal temperature of the incubator part 37 is adjusted so that the internal temperature becomes, for example, about 37 degrees C. Furthermore, the gas concentration within the incubator part 37 is adjusted by appropriately adding CO2 to the air. If necessary, the humidity may be adjusted by the incubator part 37 so as to become about 100%.
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The iPS cell establishment device 11 is similar in configuration to the iPS cell automatic culture device 20 and the differentiated cell automatic culture device 30. That is to say, the iPS cell establishment device 11 includes a housing 13A illustrated in
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One example of the sterilizing device 1 may include a sterilizing device which sterilizes the interior of the first airtight container 70 by supplying a sterilizing gas such as a hydrogen peroxide gas or a high-temperature gas into the first airtight container 70. Another example of the sterilizing device 1 may include a sterilizing device which sterilizes the interior of the first airtight container 70 by irradiating, for example, γ rays or ultraviolet rays from the outside while keeping the first airtight container 70 in a sealed state. In addition, before the first airtight container 70 is loaded from the outside, the interior of the first airtight container 70 may be sterilized using, for example, γ rays or ultraviolet rays. The liquid culture medium or the like sometimes contains protein or the like which is broken by γ rays or ultraviolet rays. In this case, it is desirable that sterilization is performed by a sterilizing gas such as a hydrogen peroxide gas, a high-temperature gas or the like.
Brief descriptions will be made on an analysis method performed in the iPS cell analysis device 80 and the differentiated cell analysis device 85. Some of the iPS cells cultured in the iPS cell automatic culture device 20 (accommodated within the second airtight container 75) are appropriately taken out from the iPS cell automatic culture device 20 by the transfer part 60 and are transferred to the loading part 81 of the iPS cell analysis device 80. Then, the culture state (e.g., the DNA state) of the iPS cells is analyzed within the iPS cell analysis device 80. Unlike the inspection performed within the iPS cell automatic culture device 20, the analysis performed in the iPS cell analysis device 80 is a destructive inspection which measures the amount of proteins or amino acids. Thus, the iPS cells used in the analysis are discarded without being returned to the iPS cell automatic culture device 20. Similarly, some of the differentiated cells cultured in the differentiated cell automatic culture device 30 (accommodated within the second airtight container 75) are appropriately taken out from the differentiated cell automatic culture device 30 by the transfer part 60 and are transferred to the loading part 86 of the differentiated cell analysis device 85. Then, the culture state (e.g., the DNA state) or the like of the differentiated cells is analyzed within the differentiated cell analysis device 85. Unlike the inspection performed within the differentiated cell automatic culture device 30, the analysis performed in the differentiated cell analysis device 85 is a destructive inspection which measures the amount of proteins or amino acids. Thus, the differentiated cells used in the analysis are discarded without being returned to the differentiated cell automatic culture device 30.
Each of the cell inspection removal part 25 of the iPS cell automatic culture device 20 and the cell inspection removal part 35 of the differentiated cell automatic culture device 30 includes a cell inspection part 25a or 35a which automatically determines the quality of colonies of cells by imaging the colonies of cells with an imaging part such as, e.g., an electronic microscope, and analyzing an image obtained by the imaging part, and a cell removal part 25b or 35b which peels off defective cells detected by the cell inspection part 25a or 35a.
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The device engineering system 130 illustrated in
The manufacturing execution system 140 illustrated in
Different kinds of information are provided in real time to the memory part 160 illustrated in
As illustrated in
The display part 211 of the external computer 210 installed in the cell ordering party 200 is able to read the information stored in the memory part 160. The display part 211 is able to read the aforementioned information illustrated as being stored in the memory part 160, namely the cell state, such as the growth situation and quality, of the cells cultured in the automatic culture devices 20 and 30 managed by the product management system 120, the profile data of the cells managed by the product management system 120, the temperature, humidity, gas concentration and operating situation of each of the iPS cell establishment device 11, the iPS cell automatic culture device 20, the differentiated cell automatic culture device 30, the storage device 40, the iPS cell analysis device 80 and the differentiated cell analysis device 85 managed by the device engineering system 130, the information on the transfer system devices such as the container transfer part 60 or the like managed by the manufacturing execution system 140, and so forth. The reading of the information may be freely carried out without restriction. Alternatively, a certain restriction may be imposed so that only the information on the cells handled by the cell ordering party 200 can be read.
Furthermore, the automatic culture system 110 manages a cell-forwarding-available time period in which the cells can be forwarded from the cell culture factory 100, based on the information on the product management system 120, the device engineering system 130, the manufacturing execution system 140, and the like. The memory part 160 can store the cell-forwarding-available time period sent in real time from the automatic culture system 110. The display part 211 can display the cell-forwarding-available time period stored in the memory part 160.
In the case where the state of the cells cultured in the automatic culture devices 20 and 30 is determined based on the image acquired by an imaging part such as an electronic microscope or the like, it is possible to figure out the health state of cells from the density of colonies of cells, the external shape of colonies of cells and the like. More specifically, the cell ordering party 200 such as a hospital or a pharmaceutical company can determine the health state of the cells by checking the image acquired by the imaging part of the cell inspection part 25a or 35a using the display part 211 of the external computer 210 installed in a hospital or the like. Instead of this aspect, the heath state of the cells may be automatically determined by a determination part (to be described later) of the automatic culture system 110. The determination result may be displayed on the display part 211 of the external computer 210.
The automatic culture system 110 may include a determination part which automatically determines the quality of the cells cultured in the automatic culture devices 20 and 30. In the case where this aspect is employed in this embodiment, the control part 29 of the iPS cell automatic culture device 20, the control part 39 of the differentiated cell automatic culture device 30, the control part 80a of the iPS cell analysis device 80 and the control part 85a of the differentiated cell analysis device 85 serve as the determination part. The determination part may determine the health state of cells from the density of colonies of cells, the external shape of colonies of cells and the like based on the image acquired by the imaging part of the cell inspection part 25a or 35a, may determine the health state of cells by observing a metabolite such as a consumption amount of glucose and an emission amount of a lactic acid, may determine the health state of cells from the viewpoint of whether the amount of a given protein steadily increases in the differentiated cells, or may determine the health state of cells from the presence or absence of a non-differentiated marker in the non-differentiated iPS cells. Incidentally, in the case where the health state of the cells is determined using the image acquired by the imaging part such as an electronic microscope or the like, the cells are determined to be healthy if the density of colonies of cells is dense, and the cells are determined to be unhealthy if the density of colonies of cells is sparse. Furthermore, the cells are determined to be healthy if the external shape of colonies of cells is a clean substantially-circular shape, and the cells are determined to be unhealthy if the external shape of colonies of cells is a distorted shape having irregularities.
In the foregoing descriptions, it has been disclosed a determination may be made on whether the cross-cells can be transplanted into the body of a patient depending on, for example, whether the immune type of a patient is the same as the immune type of the cells. However, it may be possible to employ an aspect in which it is automatically determined whether the cross-cells can be transplanted into the body of a target patient. In this case, it is reasonable to employ an aspect in which, for example, when the immune type of a patient is inputted from the manipulation part 212 by the cell ordering party 200 such as a hospital or the like, the automatic culture system 110 or the host computer system 150 picks up a cell corresponding to the immune type by referring to the profile data of cells.
A modification of the aforementioned embodiment will be described with reference to
First, the manufacturing execution system 140 issues a loading instruction of the first airtight container 70 to a transfer system device. If the loading instruction is received, the first airtight container 70 mounted with empty second airtight containers 75 is loaded into the automatic culture device 20 or 30. Then, the manufacturing execution system 140 instructs the automatic culture device 20 or 30 to start to culture. Thus, the automatic culture device 20 or 30 starts culture of cells. The culture start instruction sent from the manufacturing execution system 140 to the automatic culture device 20 or 30 may include information on the parameters, the process recipe and the like required in the culture. During the culture of cells, the automatic culture device 20 or 30 appropriately reports the in-device operating situation to the device engineering system 130 and appropriately reports the in-device analysis result of cells to the product management system 120. If the culture of cells is completed, the automatic culture device 20 or 30 reports the culture completion to the manufacturing execution system 140. If the culture completion is reported, the manufacturing execution system 140 instructs the container transfer part 60 to unload the first airtight container 70 from the automatic culture device 20 or 30. If this instruction is received, the first airtight container 70 mounted with the second airtight containers 75 which have undergone the culture process is unloaded from the automatic culture device 20 or 30 and is loaded into the storage device 40 or the cell analysis device 80 or 85. The analysis result of the cells loaded into the cell analysis device 80 or 85 is reported from the cell analysis device 80 or 85 to the product management system 120.
The host computer system 150 analyzes the cell information obtained from the product management system 120 and the device information obtained from the device engineering system 130. The necessary parameters and the process recipe are corrected pursuant to the analysis result and are fed back to the manufacturing execution system 140.
The manufacturing execution system 140 issues a loading instruction of the first airtight container 70 of the next lot to the transfer system device. If the loading instruction is received, the first airtight container 70 mounted with empty second airtight containers 75 is loaded into the automatic culture device 20 or 30. Then, the manufacturing execution system 140 instructs the automatic culture device 20 or 30 to start to culture. Thus, the automatic culture device 20 or 30 starts to culture. The culture start instruction sent from the manufacturing execution system 140 to the automatic culture device 20 or 30 may include information on the corrected parameters, the corrected process recipe and the like required in the culture.
With this configuration, it is possible to correct an inter-device error or fluctuation and a minute change of a cell culture environment, which makes it possible to maintain and control the quality of cells.
Another modification differing from the aforementioned aspect will be described by taking, as an example, the operation within the iPS cell automatic culture device 20. A plurality of second airtight containers 75 that accommodates iPS cells under culture is mounted within the incubator part 27. If the iPS cells are cultured for a predetermined period of time, the replacement of a liquid medium and the inspection of a liquid medium are performed. The inspection of a liquid medium is performed by the medium analysis part 24. As a result of inspection, if it is determined that the iPS cells are defective, the second airtight containers 75 are discarded. The result of inspection of a liquid medium is sent to the product management system 120.
Furthermore, if the iPS cells are cultured for a predetermined period of time, an inspection/removal work of the iPS cells is performed. The inspection/removal work is performed by the cell inspection removal part 25. The inspection is performed for every cell colony. If the inspection result indicates that the iPS cells are defective, the target cell colony existing in the second airtight container 75 is selectively removed. Depending on the inspection result, the second airtight container 75 containing the target colony may be discarded. The inspection result obtained in the cell inspection removal part 25 is sent to the product management system 120. Furthermore, the analysis in the cell analysis device 80 may be performed as a sampling inspection. The analysis result obtained in the cell analysis device 80 is sent to the product management system 120. Then, a seeding/subculturing work is performed. The seeding/subculturing work is performed by sampling the iPS cells from the second airtight container 75 which has undergone the culture and seeding of the iPS cells in a plurality of empty second airtight containers 75. The seeding/subculturing work may be performed simultaneously with the replacement of a liquid medium or the inspection of a liquid medium. The respective processes described above are carried out by transferring the second airtight containers 75 to the respective process parts with the in-device transfer part 23.
In this configuration, the various kinds of information sent to the product management system 120 are used in determining the quality of a liquid medium, feeding back the inspection result (the culture time, the medium adjustment, etc.), displaying an alert based on the inspection result, indicating the cleaning (maintenance) or the like. Since the information from a plurality of iPS cell automatic culture devices 20 is aggregated in the product management system 120, it is possible to perform the management or correction of an inter-device quality variation and efficient scheduling.
Next, descriptions will be made on the effects not yet mentioned or the especially important effects among the effects achieved by this embodiment having the aforementioned configuration.
According to this embodiment, the automatic culture system 110 sends the state of the cells managed by the product management system 120 to the memory part 160 of the host computer system 150 in real time. The state of the cells cultured in the automatic culture devices 20 and 30 is stored in the memory part 160 in real time (see
Furthermore, in this embodiment, the cell ordering party 200 such as a hospital or a pharmaceutical company can order the cells of the cell culture factory 100 through the host computer system 150 by inputting an order from the manipulation part 212 of the external computer 210 (see
Furthermore, in this embodiment, the automatic culture system 110 sends the profile data of cells managed by the product management system 120 to the memory part 160 in real time. The profile data of the cells cultured in the automatic culture devices 20 and 30 are stored in the memory part 160 in real time (see
Furthermore, in this embodiment, in the case of employing the determination part which automatically determines the quality of the cells cultured in the automatic culture devices 20 and 30, the cell ordering party 200 such as a hospital or a pharmaceutical company can figure out the determination result of the quality of cells in the determination part through the display part 211 of the external computer 210. Thus, the cell ordering party 200 can automatically figure out the quality of cells without having to make a determination by itself. As a result, it is possible to prevent the cell ordering party 200 from making erroneous determination and to alleviate the burden borne by the cell ordering party 200.
Furthermore, in this embodiment, the automatic culture system 110 sends the information on the iPS cell establishment device 11, the iPS cell automatic culture device 20, the differentiated cell automatic culture device 30, the storage device 40, the iPS cell analysis device 80 and the differentiated cell analysis device 85 managed by the device engineering system 130 to the memory part 160 in real time. The information on the iPS cell establishment device 11, the iPS cell automatic culture device 20, the differentiated cell automatic culture device 30, the storage device 40, the iPS cell analysis device 80 and the differentiated cell analysis device 85 is stored in the memory part 160 in real time (see
In this embodiment, the automatic culture system 110 sends the information on the transfer system device such as the container transfer part 60 or the like managed by the manufacturing execution system 140 to the memory part 160 in real time. The information on the container transfer part 60 is stored in the memory part 160 in real time (see
In this embodiment, the automatic culture system 110 sends the forwarding-available time period of the cells cultured in the automatic culture devices 20 and 30 to the memory part 160 in real time. The forwarding-available time period of the cells is stored in the memory part 160 in real time (see
In addition, in this embodiment, a hospital and a pharmaceutical company are taken as examples of the cell ordering party 200. In the case where the hospital is the cell ordering party 200, it is assumed that the iPS cells or differentiated cells as ordered are returned into the body of an actual patient (namely, a human). Thus, in this case, there is a need to culture the iPS cells or the differentiated cells at a higher quality. The aspect of fully automatically culturing the iPS cells or the differentiated cells as in this embodiment is very beneficial.
Finally, the foregoing descriptions of the respective embodiments and the disclosure of the drawings are nothing more than one example for describing the present disclosure recited in the claims. The present disclosure recited in the claims shall not be limited by the foregoing descriptions of the respective embodiments and the disclosure of the drawings. Furthermore,the descriptions of the respective embodiments and the disclosure of the drawings may be combined unless a conflict arises.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2013-243210 | Nov 2013 | JP | national |
This application is a Continuation Application of PCT International Application No. PCT/JP2014/080976, filed Nov. 21, 2014, which claimed the benefit of Japanese Patent Application No. 2013-243210, filed Nov. 25, 2013, the entire content of each of which is hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/JP2014/080976 | Nov 2014 | US |
| Child | 15162902 | US |
