US-20260125631-A1 - SIMULATION APPARATUS, SIMULATION SYSTEM, AND SIMULATION METHOD FOR SIMULATING CELL PROLIFERATION BY A CELL CULTURE APPARATUS

US20260125631A1US 20260125631 A1US20260125631 A1US 20260125631A1US-20260125631-A1

Abstract

A simulation apparatus configured to simulate a change in concentration of protein in an inner circulation path using a supply speed, an exchange speed, and a deterioration speed, a predetermined or selected culture condition being applied in the circulation path, the supply speed being a first speed at which a first concentration of the protein in the circulation path changes as a result of the supply of the culture medium to the circulation path, the exchange speed being a second speed at which a second concentration of the protein in the circulation path changes as a result of inflow and outflow of the culture medium between the circulation path and an outer region of the circulation path, and the deterioration speed being a third speed at which a third concentration of the protein in the circulation path changes as a result of deterioration of the protein.

Inventors

Nozomu Yamazaki

Assignees

TERUMO KABUSHIKI KAISHA

Dates

Publication Date: 20260507
Application Date: 20251212
Priority Date: 20230616

Claims (20)

1 . A simulation apparatus for simulating cell proliferation in a cell culture apparatus, the simulation apparatus comprising: a simulation execution unit configured to simulate a change in concentration of a protein in a circulation path of the cell culture apparatus using a supply speed, an exchange speed, and a deterioration speed, a predetermined or selected culture condition being applied in the circulation path, the supply speed being a first speed at which a first concentration of the protein in the circulation path changes as a result of the supply of a culture medium to the circulation path, the exchange speed being a second speed at which a second concentration of the protein in the circulation path changes as a result of inflow and outflow of the culture medium between the circulation path and an outer region of the circulation path, and the deterioration speed being a third speed at which a third concentration of the protein in the circulation path changes as a result of deterioration of the protein.
2 . The simulation apparatus of claim 1 , further comprising: a display control unit configured to control a display unit of the cell culture apparatus including to display information according to the concentration change obtained by the simulation.
3 . The simulation apparatus of claim 1 , wherein the simulation execution unit is further configured to use a consumption speed when simulating the change in the concentration of the protein in the circulation path, the consumption speed being a fourth speed at which a fourth concentration of the protein in the circulation path changes as a result of consumption of the protein by the cells.
4 . The simulation apparatus of claim 1 , wherein the simulation execution unit is further configured to use a discard speed when simulating the change in the concentration of the protein changes in the circulation path, the discard speed being a fifth speed at which a fifth concentration of the protein in the circulation path changes as a result of a part of the culture medium being discarded via the circulation path.
5 . The simulation apparatus of claim 1 , wherein the simulation execution unit is further configured to use an adsorption rate when simulating the change in concentration of the protein in the circulation path, the adsorption rate being a sixth concentration of protein in the circulation path that cannot be consumed by the cells because the sixth concentration of protein is adsorbed, aggregated, or deposited within or outside of the circulation path.
6 . The simulation apparatus of claim 1 , wherein the circulation path is an inner circulation path defined by an inner channel of a hollow fiber membrane of the cell culture apparatus and the cell culture apparatus is configured to supply a culture medium not containing the protein to an outer circulation path, the outer circulation path being defined by a region between the hollow fiber membrane and a housing that stores the hollow fiber membrane.
7 . The simulation apparatus of claim 6 , wherein the cells proliferated by the cell culture apparatus include adherent cells, and the cell culture apparatus is configured to discard the culture medium via a waste liquid flow path that is in communication with the inner circulation path.
8 . The simulation apparatus of claim 6 , wherein the cells proliferated by the cell culture apparatus include floating cells, and the cell culture apparatus is configured to discard the culture medium via a waste liquid flow path that is in communication with the outer circulation path.
9 . The simulation apparatus of claim 1 , wherein the circulation path is an inner circulation path defined by an inner channel of a hollow fiber membrane of the cell culture apparatus and the cell culture apparatus further includes an outer circulation path defined between the hollow fiber membrane and a housing that stores the hollow fiber membrane, and if a part of the culture medium is discarded via the outer circulation path during cell culture, the simulation execution unit is further configured to simulate a change in concentration of the protein in the outer circulation path using the exchange speed, the deterioration speed, and a discard speed, the discard speed being a speed at which a concentration of the protein changes in the outer circulation as a result of a part of the culture medium being discarded via the outer circulation path.
10 . A simulation system for simulating cell proliferation in a cell culture apparatus, the simulation system comprising: a simulation execution unit configured to simulate a change in concentration of a protein in an inner circulation path of the cell culture apparatus using a supply speed, an exchange speed, and a deterioration speed, a predetermined or selected culture condition being applied in the inner circulation path, the cell culture apparatus including a hollow fiber membrane and the inner circulation path defined by an inner channel of the hollow fiber membrane, the supply speed being a first speed at which a first concentration of the protein in the inner circulation path changes as a result of the supply of a culture medium to the inner circulation path, the exchange speed being a second speed at which a second concentration of the protein in the inner circulation path changes as a result of inflow and outflow of the culture medium between the inner circulation path and an outer region of the inner circulation path, and the deterioration speed being a third speed at which a third concentration of the protein in the inner circulation path changes as a result of deterioration of the protein; and a display control unit configured to control a display unit of the cell culture apparatus including to display information according to the change in concentration obtained by the simulation.
11 . The simulation system of claim 10 , wherein the simulation execution unit is further configured to use at least one of a consumption speed, a discard speed, and an adsorption rate when simulating the change in the concentration of the protein in the circulation path, the consumption speed being a fourth speed at which a fourth concentration of the protein in the circulation path changes as a result of consumption of the protein by the cells, the discard speed being a fifth speed at which a fifth concentration of the protein in the circulation path changes as a result of a part of the culture medium being discarded via the circulation path, and the adsorption rate being a sixth concentration of protein in the circulation path that cannot be consumed by the cells because the sixth concentration of protein is adsorbed, aggregated, or deposited within or outside of the circulation path.
12 . A simulation method for simulating cell proliferation in a cell culture apparatus, the simulation method comprising: simulating a change in concentration of a protein in a circulation path of the cell culture apparatus using a supply speed, an exchange speed, and a deterioration speed, a predetermined or selected culture condition being applied in the circulation path, the supply speed being a first speed at which a first concentration of the protein in the circulation path changes as a result of the supply of a culture medium to the circulation path, the exchange speed being a second speed at which a second concentration of the protein in the circulation path changes as a result of inflow and outflow of the culture medium between the circulation path and an outer region of the circulation path, and the deterioration speed being a third speed at which a third concentration of the protein in the circulation path changes as a result of deterioration of the protein.
13 . The simulation method of claim 12 , further comprising: displaying information according to the change in concentration obtained by the simulation on a display unit of the cell culture apparatus.
14 . The simulation method of claim 12 , wherein the simulating of the change in the concentration of the protein in the circulation path of the cell culture apparatus further uses a consumption speed, the consumption speed being a fourth speed at which a fourth concentration of the protein in the circulation path changes as a result of consumption of the protein by the cells.
15 . The simulation method of claim 12 , wherein the simulating of the change in the concentration of the protein in the circulation path of the cell culture apparatus further uses a discard speed, the discard speed being a fifth speed at which a fifth concentration of the protein in the circulation path changes a result of a part of the culture medium being discarded via the circulation path.
16 . The simulation method of claim 12 , wherein the simulation of the change in the concentration of the protein in the circulation path of the cell culture apparatus further uses an adsorption rate, the adsorption rate being a sixth concentration of protein in the circulation path that cannot be consumed by the cells because the sixth concentration of protein is adsorbed, aggregated, or deposited within or outside of the circulation path.
17 . The simulation method of claim 12 , wherein the circulation path is an inner circulation path defined by an inner channel of a hollow fiber membrane of the cell culture apparatus, and the method further includes supplying a culture medium not containing the protein to an outer circulation path, the outer circulation path being defined by a region between the hollow fiber membrane and a housing that stores the hollow fiber membrane.
18 . The simulation method of claim 16 , wherein the cells proliferated by the cell culture apparatus include adherent cells, and the cell culture apparatus is configured to discard the culture medium via a waste liquid flow path that is in communication with the circulation path.
19 . The simulation method of claim 16 , wherein the cells proliferated by the cell culture apparatus include floating cells, and the cell culture apparatus is configured to discard the culture medium via a waste liquid flow path that is in communication with the outer circulation path.
20 . The simulation method of claim 12 , wherein the circulation path is an inner circulation path defined by an inner channel of a hollow fiber membrane of the cell culture apparatus and the cell culture apparatus further includes an outer circulation path defined between the hollow fiber membrane and a housing that stores the hollow fiber membrane, if a part of the culture medium is discarded via the outer circulation path during cell culture, the simulating of the change in the concentration of the protein in the circulation path of the cell culture apparatus further includes using a discard speed, the discard speed being a speed a concentration of the protein changes in the outer circulation as a result of a part of the culture medium being discarded via the outer circulation path.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a continuation of the International Patent Application No. PCT/JP2024/021739 filed Jun. 14, 2024, which designated the U.S. and claims the benefit of priority from Japanese Patent Application No. JP2023098863 filed Jun. 16, 2023. The entire disclosures of the above-identified applications are incorporated herein by reference. FIELD The present invention relates to a simulation apparatus, a simulation system, and a simulation method for simulating cell proliferation by a cell culture apparatus. BACKGROUND JP 2020-171241 A discloses a cell culture apparatus. including a bioreactor, a supply unit, a recovery unit, and a plurality of flow paths. Some flow paths of the cell culture apparatus form a circulation path with the bioreactor. The supply unit is configured to supply a cell-containing solution and a culture medium (culture solution) to the bioreactor, which cultures cells. During cell culture, a part of the culture medium (e.g., first culture medium) circulates in the circulation path and a part of the culture medium (e.g., second culture medium) is discharged as a waste liquid. The recovery unit is configured to recover the cultured cells. Supply of nutrients (e.g., glucose, glutamine, various amino acids, the like, or any combination thereof), supply of gases (e.g., oxygen, carbon dioxide, the like, or any combination thereof), and discharge of waste products (e.g., lactic acid, ammonia, the like, or any combination thereof) are important for cell culture. Protein supply is also important for cell culture. Therefore, bovine serum (which includes albumin and growth factors), growth factors, cytokines, the like, or any combination thereof are added to the culture medium. When protein supplied to the cell is insufficient, the cell does not proliferate. In contrast, when the amount of protein to be supplied to the cell is too large, the cell proliferation may be inhibited. Furthermore, a unit price of some proteins (e.g., growth factors, cytokines, and the like) is often high. Accordingly, it is desirable to appropriately control the amount of protein to be supplied to cells. SUMMARY At least one example embodiment relates to a simulation apparatus that is configured to execute a simulation of cell proliferation in a cell culture apparatus, where the cell culture apparatus is configured to supply a culture medium (e.g., containing protein) to a circulation path that is defined by an inner pore of a cylindrical hollow fiber membrane (i.e., an inner circulation path) such that cells are cultured in the inner pore. The simulation apparatus may include a simulation execution unit that is configured to simulate a change in concentration of the protein in the inner circulation path while cell proliferation occurs under a predetermined or selected culture condition at least using a supply speed which is a speed at which the concentration of the protein changes in the inner circulation path as a result of a culture medium being supplied to the inner circulation path, an exchange speed which is a speed at which the concentration of the protein changes in the inner circulation path as a result inflow and outflow of the culture medium between an inside of the inner pore and an outside of the inner pore via the hollow fiber membrane, and a deterioration speed which is a speed at which the concentration of the protein changes in the inner circulation path due to deterioration of the protein. From a relationship between a molecular weight cutoff of the hollow fiber membrane and a size of protein, a behavior of the protein diffusing into and out of the cylindrical hollow fiber membrane may differ for each type of protein. The simulation may be executed using not only the supply speed and the deterioration speed but also the exchange speed which improves the accuracy of the simulation of the change in concentration of protein. The user may appropriately control (i.e., adjust) an amount of protein by reflecting the simulation result in the real culture. In at least one example embodiment, the simulation may further include a display control unit that is configured to control a display unit of the cell culture apparatus, including, for example, to display information according to the concentration change obtained by the simulation. In at least one example embodiment, the simulation of the change in concentration of the protein in the inner circulation path may further include using a consumption speed which is a speed at which the concentration of the protein changes in the inner circulation path as a result of the consumption of the protein by the cells. In at least one example embodiment, where a part of the culture medium is discarded via the inner circulation path during cell culture, the simulation of the change in concentration of the protein in the inner circulation path may further include using a discard speed which is a speed at which the concentra