Systems and methods for controlling oxygen levels

Abstract

The sensors are configured to capture measurement data representing dissolved oxygen (DO) measurements of the environment and capacitance measurements of a medium in the environment. A memory includes computer-executable instructions. One or more processors are communicatively coupled to the one or more sensors and configured to execute the computer-executable instructions to perform operations including: using first measurement data captured by the one or more sensors to generate a model based on a relationship between a first set of DO measurements and a first set of capacitance measurements; receiving second measurement data from the one or more sensors; using the model to predict expected DO measurements based on new capacitance measurements; determining whether to use the expected DO measurements or the new DO measurements; and controlling a valve to flow a determined amount of oxygen input into the environment based on the expected DO measurements.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 062,134, filed Aug. 6, 2020, and European Patent Application No. 20315463.8, filed Nov. 20, 2020, the contents of which are hereby incorporated by reference in their entirety.

[0002] This disclosure generally relates to active environments such as bioreactors.

Background Art

[0003] A bioreactor can refer to any manufactured device or system that supports a biologically active environment. For example, a bioreactor can be a vessel in which a chemical process involving organic matter or biologically active substances derived from such organic matter is carried out. This process can be aerobic or anaerobic. These bioreactors can be cylindrical in size ranging from liters to cubic meters and can be made of stainless steel. A bioreactor can also refer to a device or system designed to grow cells or tissues in the context of cell culture. Such devices can be developed for use in tissue engineering or biochemical / bioprocess engineering. Bioreactors can be classified as batch, fed - batch or continuous (e.g., continuous stirred - tank reactor model). An example of a continuous bioreactor is a chemostat. The organic matter growing within a bioreactor can be immersed in a liquid medium or attached to the surface of a solid medium. The immersed culture can be suspended or immobilized.

[0004] Dissolved oxygen (DO) can refer to the amount of oxygen dissolved in a water source, such as a bioreactor. Depending on the application, measuring and tracking the amount of dissolved oxygen in water may be essential. When functioning in fermentation and cell culture, dissolved oxygen probes can be used to measure dissolved oxygen in bioreactors and cell cultures. Whether developing new drugs or studying the biochemistry of cells, accurate levels of dissolved oxygen may be crucial for the effective functioning of a bioreactor. Low dissolved oxygen levels in a bioreactor can cause problems with cell growth rate and nutrient uptake, which can negatively impact research and experiments. To avoid such challenges, dissolved oxygen levels can be continuously measured using dissolved oxygen sensors.

[0005] DO concentration can be highly important for the growth and production of cell cultures. Excessively high or low DO levels can have adverse effects. For example, excessively low DO levels in a bioreactor may reduce growth rates, impair nutrient uptake, and affect metabolite synthesis, potentially leading to reduced final product quality and yield. On the other hand, higher DO levels can lead to the expression of reactive oxygen species, which are highly unstable molecules that can cause cell death. Additionally, certain components of a substance may become oxidized, potentially leading to cellular mutations. [Overview of the Initiative] [Means for solving the problem]

[0006] In one embodiment, a system is provided. The system includes one or more sensors configured to acquire measurement data representing dissolved oxygen (DO) measurements of the environment and capacitance measurements of the environment's medium. The system includes computer-readable memory containing computer execution instructions. The system includes one or more processors communicatively coupled to one or more sensors and configured to execute computer executable instructions, and when one or more processors are executing computer executable instructions, the one or more processors are configured to: generate a model based on the relationship between a first set of DO measurements and a first set of capacitance measurements, using first measurement data acquired by one or more sensors during a first time interval and representing a first set of DO measurements and a first set of capacitance measurements; receive second measurement data from one or more sensors, acquired by one or more sensors during a second time interval and representing new DO measurements and new capacitance measurements; use the model to predict expected DO measurements based on the new capacitance measurements; decide whether to use the expected DO measurements or the new DO measurements to determine the oxygen input amount; and, when it is decided to use the expected DO measurements, control a valve to allow the determined oxygen input amount to flow into the environment based on the expected DO measurements. Other embodiments may include methods, devices, computer-readable media, computer program products and other technologies.

[0007] The embodiment may include some or all of the following configurations, or none of them. Determining whether to use an expected dissolved oxygen amount or a new DO amount includes: determining the rate of change of DO based on a new DO measurement and a first set of DO measurements; determining the rate of change of capacitance based on a new capacitance measurement and a first set of capacitance measurements; and deciding to use the expected DO measurement when the rate of change of DO exceeds the rate of change of capacitance by a rate of change threshold. A bioreactor comprising one or more sensors, a DO sensor and a capacitance sensor. Determining whether to use an expected DO measurement or a new DO measurement includes: comparing a new capacitance measurement with a capacitance threshold; and deciding to use the new DO measurement when the new capacitance measurement exceeds the capacitance threshold. Determining whether to use an expected DO measurement or a new DO measurement includes: comparing an expected DO measurement and a new DO measurement; and deciding to use the expected DO measurement when the expected DO measurement exceeds the new DO measurement. Receiving third measurement data from one or more sensors, which is acquired by one or more sensors during a third time interval and represents a second set of DO measurements and a second set of capacitance measurements; and updating the model based on the third measurement data. The third measurement data includes the second measurement data.

[0008] Embodiments of this disclosure can provide one or more of the following advantages: Compared to the prior art, the amount of dissolved oxygen in the environment (e.g., a bioreactor) can be controlled with increased precision and accuracy, cell culture and fermentation processes can be improved, and noise from sensor outputs can be reduced.

[0009] These and other aspects, configurations and embodiments can be represented as methods, apparatus, systems, components, program products, means or steps for performing functions, and in other ways.

[0010] These and other aspects, configurations and implementations will become apparent from the following description, including the claims. [Brief explanation of the drawing]

[0011] [Figure 1] This is a block diagram illustrating an exemplary system for controlling oxygen levels. [Figure 2] This is a flowchart illustrating an exemplary method for controlling oxygen levels. [Figure 3] This is a block diagram of an exemplary computer system used to provide computational capabilities related to the algorithms, methods, functions, processes, flows, and procedures described herein, as described herein, according to some embodiments of the herein disclosure. [Modes for carrying out the invention]

[0012] A bioreactor system (sometimes referred to herein as a bioreactor) may include a vessel having a stirrer for mixing the contents of the bioreactor system to keep the cells of the contents under homogeneous conditions for better transport of nutrients and oxygen to the desired product; baffles used to disrupt vortex formation within the vessel; a sparger for supplying oxygen (dissolved oxygen) to the growing cells; and a jacket providing an annular area for constant temperature circulation of water. The bioreactor system may also include processing mechanisms such as proportional-integral-differential controllers (PID controllers) and mass flow controllers (MFCs) for controlling and maintaining certain types of liquids or gases entering the vessel. To facilitate monitoring of dissolved oxygen (DO) in the bioreactor, a DO sensor may be used to measure the amount of DO in the bioreactor. During cell growth, the amount of oxygen demand in the bioreactor may increase, resulting in an increased continuous injection of oxygen bubbles to maintain cell growth. However, these oxygen bubbles can interact with the DO sensor, potentially giving it inaccurate readings (i.e., causing the DO sensor to measure more DO in the bioreactor than is actually present). These inaccurate readings can lead to reduced accuracy in the processing mechanism when determining the amount of DO that should be added to the bioreactor to maintain cell growth.

[0013] The systems and methods described herein can mitigate the effects of the aforementioned drawbacks. In some embodiments, a capacitance sensor is used in conjunction with a DO sensor to measure the capacitance (biomass) of a bioreactor over time. Cells with intact plasma membranes in a bioreactor (or fermenter) can be considered to act as capacitors under the influence of an electric field. The non-conductive properties of the plasma membrane allow for charge accumulation. The resulting capacitance can be measured, and this capacitance can be proportional to the amount of membrane binding in these cells. Thus, the capacitance can be used as an orthogonal measure of biomass (e.g., cell density). In some embodiments, the capacitance measured over time is used to generate a model (slope) of the relationship between the measured capacitance and oxygen demand (MFC, O2 output from actuator) in order to maintain a DO setpoint (target DO value) over time. It can be assumed that the oxygen demand per cell remains constant (i.e., the oxygen uptake rate can be derived). Therefore, as the capacitance increases, the increase in oxygen demand should increase at a constant rate (i.e., according to the oxygen uptake rate). Therefore, in some embodiments, the generated model can be used to predict the expected oxygen output in the bioreactor required to maintain the DO set point, and this expected oxygen output can be used to determine the amount of oxygen gas to be added to the bioreactor to promote cell proliferation and to match the DO set point. In some embodiments, the model is updated after a predetermined amount of time based on new measurements. In some embodiments, when new DO measurements are taken up by the DO sensor, it is determined whether to use the new DO measurements or the predicted DO measurements to determine how much oxygen is input into the bioreactor. In some embodiments, historical data of the oxygen output and its comparison with capacitance can be used to determine how much oxygen is input into the bioreactor. This can be used in cases where DO measurement noise interferes with the accurate generation of the relationship between oxygen output and capacitance.This decision can be based on a comparison between the determined rate of change of DO and the determined rate of change of capacitance, or on a comparison between the predicted DO amount and the new DO value.

[0014] The drawings show the specific arrangement or order of schematic elements, such as those representing devices, modules, instruction blocks, and data elements, for the purpose of facilitating explanation. However, those skilled in the art should understand that the specific arrangement or order of schematic elements in the drawings is not intended to imply that a specific order or sequence of processes, or separation of processes, is required. Furthermore, the inclusion of schematic elements in the drawings is not intended to imply that such elements are required in all embodiments, nor that the configurations represented by such elements are not included in or combined with other elements in some embodiments.

[0015] Furthermore, when connecting elements such as solid or dashed lines or arrows are used in drawings to illustrate connections, relationships, or associations between two or more other schematic elements, the absence of such connecting elements is not intended to imply that such connections, relationships, or associations cannot exist. In other words, some connections, relationships, or associations between elements are not shown in the drawings to avoid obscuring the disclosure. In addition, for ease of illustration, a single connecting element may be used to represent multiple connections, relationships, or associations between elements. For example, if a connecting element represents the communication of signals, data, or instructions, a person skilled in the art should understand that such an element may, as necessary, represent one or more signal paths (e.g., buses) that affect the communication.

[0016] Next, we will refer in detail to embodiments illustrated in the attached drawings. The following detailed description provides numerous specific details to give a complete understanding of the various embodiments described. However, it will be apparent to those skilled in the art that the various embodiments described can be carried out without these specific details. In other examples, well-known methods, procedures, components, circuits, and networks are not described in detail so as not to unnecessarily obscure the aspects of the embodiments.

[0017] The following describes several configurations, each of which can be used independently of the others or in any combination of other configurations. However, no single individual configuration may address any of the problems discussed above, or it may address only one of them. Some of the problems discussed above may not be fully resolved by any of the configurations described herein. Headings may be provided, but data related to a particular heading that is not found in the section containing that heading may be found elsewhere in this specification.

[0018] Figure 1 is a block diagram showing an exemplary system 100 for controlling oxygen levels. The system 100 includes one or more sensors 120, a sparger 130, a control valve 140, and a computer processor 110.

[0019] One or more sensors 120 include a DO sensor. In some embodiments, the DO sensor includes an electrochemical DO sensor such as a polarographic sensor or a galvanic sensor. In some embodiments, the DO sensor includes a photo-DO sensor. The DO sensor is configured to measure the amount of DO in the bioreactor 150 and to generate measurement data representing the measured amount of DO. One or more sensors 120 also include a capacitance sensor. The capacitance sensor is configured to measure the amount of capacitance of the medium in the bioreactor (e.g., cell mass) and to generate measurement data representing the measured amount of capacitance.

[0020] The control valve 140 is in fluid communication with the oxygen supply line, and the flow of oxygen into the bioreactor 150 through the sparger 130 can be adjusted using the control valve 140. As will be described later, the valve 140 can be controlled by the computer processor 110.

[0021] The computer processor 110 is coupled to one or more sensors 120 and includes computer-readable memory 111 and computer-readable instructions 112. The computer-readable memory 111 (or computer-readable medium) includes, but is not limited to, any form of data storage technology suitable for the local technical environment, including semiconductor-based memory devices, magnetic memory devices and systems, optical memory devices and systems, fixed memory, removable memory, disk memory, flash memory, dynamic random access memory (DRAM), static random access memory (SRAM), electrically erasable programmable read-only memory (EEPROM), etc. In some embodiments, the computer-readable memory 111 includes code segments having executable instructions.

[0022] The computer processor 110 may include a general-purpose processor, a central processing unit (CPU), and / or at least one application-specific integrated circuit (ASIC). The computer processor 110 may also include a general-purpose programmable microprocessor, a dedicated programmable microprocessor, a digital signal processor (DSP), a programmable logic array (PLA), a field-programmable gate array (FPGA), dedicated electronic circuitry, or a combination thereof. The computer processor 110 is configured to execute program code means such as computer executable instructions 112. In some embodiments, the computer processor 110 includes all or part of a PID controller. In some embodiments, the computer processor 110 includes all or part of a mass flow controller.

[0023] When executing a computer executable instruction 112, the computer processor 110 is configured to receive measurement data from one or more sensors 120 and, based on the measurement data, generate a model based on the relationships between multiple oxygen outputs and multiple capacitance measurements. In some embodiments, before generating the model, the computer processor is configured to apply an exponent (e.g., a process variable (PV) filter) to the measurement data to reduce a predetermined amount of noise in the measurement data and to correct the measured values ​​of the measurement data based on the predetermined amount of noise. The predetermined amount of noise can be determined based on known design parameters and testing of one or more sensors 120 and other system parameters (i.e., based on testing and calibration of one or more sensors 120, it can be determined how much noise one or more sensors 120 inherently adds to the measurement data). In some embodiments, one or more sensors 120 are configured to acquire measurement data at measurement time intervals. For example, one or more sensors 120 may be configured to acquire measurement data every 5 seconds, every 10 seconds, or every 15 seconds. Next, the computer processor 110 is configured to plot a set of DO measurements against a set of capacitance measurements taken during a predetermined time interval (e.g., one hour) to generate a slope. For example, if one or more sensors 120 are configured to take measurement data every 5 seconds, the computer processor 110 may plot the DO measurement taken at t0 (time = 0) against the capacitance measurement taken at t0, the DO measurement taken at t1 (time = 5 seconds) against the capacitance measurement taken at t1, the DO measurement taken at t2 (time = 10 seconds) against the capacitance measurement taken at t2, and so on, over the course of one hour. In some embodiments, the model represents the slope, and the computer processor 110 is configured to determine the average of the slope. In some embodiments, the model can be updated with new measurements after a predetermined amount of time (e.g., every 720 seconds).For example, measurements taken every 720 seconds after an hour time interval can be added to the model, and a new slope average can be determined (this is a moving average function that allows new values to push out old values in the array and enables the slope to change slowly. 720 seconds can be changed).

[0024] Once the model is generated, the computer processor 110 is configured to receive new measurement data (including corresponding new measurements for DO, capacitance, and oxygen output) and to use the model to determine the expected oxygen output based on the new capacitance measurement. For example, for each new capacitance measurement, the computer processor 110 can apply the model to determine the expected oxygen output value using the determined average slope. The computer processor 110 is then configured to decide whether to use the new oxygen output value or the expected oxygen output value and to determine how much oxygen should flow through the sparger 130 into the bioreactor 150. In some embodiments, this involves comparing the rate of change (RoC) of DO to the capacitance RoC. For example, the RoC between DO measurements can be compared to the RoC between capacitance measurements. In some embodiments, if the DO RoC is higher than the capacitance RoC, the expected DO measurement is used to determine the amount of DO to add to the bioreactor. In some embodiments, the capacitance RoC is the actual capacitance RoC converted to oxygen flow rate units. For example, capacitance RoC can be the actual change in capacitance over time multiplied by the previously determined oxygen output / capacitance slope to obtain the expected oxygen output RoC. In some embodiments, if the expected oxygen output RoC is higher than the oxygen output RoC, the expected oxygen output measurement is used to determine the amount of oxygen to add to the bioreactor 150. If the expected oxygen output RoC is less than or equal to the oxygen output RoC, the new oxygen output is used to determine the amount of oxygen to add to the bioreactor 150. In some embodiments, if the expected oxygen output is higher than the new oxygen output, the determined oxygen output is used to determine the amount of oxygen to add to the bioreactor 150. In some embodiments, if the new capacitance measurement is higher than the capacitance threshold, the new oxygen output is used to determine the amount of oxygen to add to the bioreactor 150. The capacitance threshold can be based on the growth stage of the bioreactor 150, ensuring that the new oxygen output is used after the growth stage is complete.In some embodiments, as described above, the model is updated using the new oxygen output and the new capacitance measurement value.

[0025] When the type of oxygen output for use (i.e., either the expected oxygen output or the new oxygen output) is determined, the computer processor 110 is configured to determine the amount of oxygen to be added to the bioreactor based on the determined oxygen output and the desired amount of oxygen output for the bioreactor 150. The desired amount of oxygen output can be based on, for example, the requirements for effective cell culture conditions. The computer processor 110 is configured to operate the valve 140 so that oxygen enters the bioreactor 150 through the sparger 130.

[0026] FIG. 2 is a flowchart showing an exemplary method 200 for controlling the oxygen level. In some embodiments, the method 200 is executed by the computer processor 110 discussed above with reference to FIG. 1. The method 200 includes generating a model based on first measurement data (block 210); receiving second measurement data (block 220); predicting an expected oxygen output (block 230); determining whether to use the expected oxygen output or a new oxygen output (block 240); and controlling a valve based on the expected oxygen output or the new oxygen output (block 250).

[0027] Generally, the process 200 can be considered to perform operations including transmitting the DO measurement value to a PID to generate an oxygen output; obtaining a capacitance measurement value; establishing a slope between the oxygen output and the capacitance; generating a moving average and / or exponential filter of the slope; multiplying the capacitance by the moving average / exponentially filtered slope value to determine the expected oxygen output; determining whether to use the expected oxygen output or a new oxygen output; and controlling a valve (actuator) based on the expected oxygen output or the new oxygen output value.

[0028] In block 210, measurement data representing a set of DO measurements and a set of capacitance measurements acquired over a predetermined time interval is received from one or more sensors (e.g., sensor 120 shown in Figure 1). The oxygen output is plotted against the corresponding capacitance measurements, and the average slope is determined based on the plot.

[0029] In block 220, second measurement data is received, representing a new DO measurement and a new capacitance measurement.

[0030] In block 230, the average slope is applied to the new capacitance measurement to determine the expected oxygen output.

[0031] In block 240, when determining the amount of oxygen to be added to the bioreactor, it is determined whether to use the expected oxygen output or a new oxygen output. In some embodiments, the decision is based on a comparison of DO RoC and capacitance RoC, as described above with reference to Figure 1. In some embodiments, the decision is based on a comparison of the expected oxygen output and a new oxygen output, as described above with reference to Figure 1.

[0032] In block 250, if it is determined to use the expected oxygen output, the control valve is controlled to allow oxygen into the bioreactor based on the expected oxygen output. If it is determined to use a new oxygen output, the control valve is controlled to allow oxygen into the bioreactor based on the new oxygen output.

[0033] Figure 3 is a block diagram of an exemplary computer system 500 used to provide computational capabilities related to the algorithms, methods, functions, processes, flows, and procedures described herein, according to several embodiments of the present disclosure. The illustrated computer 502 is intended to encompass any computing device, such as a server, desktop computer, laptop / notebook computer, wireless data port, smartphone, personal data assistant (PDA), tablet computing device, or one or more processors (including physical instances, virtual instances, or both) within such devices. The computer 502 may include input devices such as keypads, keyboards, and touchscreens that can accept user information. The computer 502 may also include output devices that can transmit information related to the operation of the computer 502. The information may include digital data, visual data, audio information, or a combination of information. The information may be presented in a graphical user interface (UI) (or GUI).

[0034] Computer 502 can act as a client, network component, server, database, or component of a computer system for performing the subject matter described in this disclosure. The illustrated computer 502 is coupled to network 530 in a communicative manner. In some embodiments, one or more components of computer 502 can be configured to operate in different environments, including cloud computing-based environments, local environments, global environments, and combinations of environments.

[0035] At a high level, computer 502 is an electronic computing device capable of receiving, transmitting, processing, storing, and managing data and information relating to the described subject. According to some embodiments, computer 502 may also include, or be communicably coupled with, an application server, an email server, a web server, a caching server, a streaming data server, or a combination of servers.

[0036] Computer 502 can receive requests via network 530 from client applications (for example, running on another computer 502). Computer 502 can respond to incoming requests by processing them using software applications. Requests can also be sent to computer 502 from internal users (e.g., command consoles), external (or third parties), automated applications, entities, individuals, systems, and computers.

[0037] Each component of computer 502 can communicate using the system bus 503. In some embodiments, any or all components of computer 502, including hardware or software components, can interface with each other or with interface 505 (or a combination of both) via the system bus 503. The interface can be an application programming interface (API) 512, a service layer 513, or a combination of API 512 and service layer 513. API 512 can include specifications for routines, data structures, and object classes. API 512 may be independent of or dependent on a computer language. API 512 can refer to a complete interface, a single function, or a set of APIs.

[0038] Service Layer 513 can provide software services to Computer 502 and other components (whether shown or not) communicatively coupled to Computer 502. The functionality of Computer 502 is accessible to all service consumers using this service layer. Software services such as those provided by Service Layer 513 can provide reusable and defined functionality through a defined interface. For example, the interface may be software written in a language that provides data in Java®, C++, or Extensible Markup Language (XML) format. Although illustrated as an integrated component of Computer 502, in alternative embodiments, API 512 or Service Layer 513 may be a standalone component in relation to other components of Computer 502 and other components communicatively coupled to Computer 502. Furthermore, any or all parts of API 512 or Service Layer 513 may be implemented as a child module or submodule of another software module, enterprise application, or hardware module without departing from the scope of this disclosure.

[0039] Computer 502 includes interface 504. Although illustrated as a single interface 504 in Figure 3, two or more interfaces 504 may be used depending on the specific needs, requirements, or implementations of computer 502 and the functions described. Interface 504 can be used by computer 502 to communicate with other systems (whether illustrated or not) connected to network 530 in a distributed environment. Generally, interface 504 may include or be implemented using software or hardware (or a combination of software and hardware) encoded logic that is capable of communicating with network 530. More specifically, interface 504 may include software that supports one or more communication protocols related to communication. Thus, network 530 or interface hardware can be made capable of communicating physical signals inside and outside computer 502 as illustrated.

[0040] The computer 502 includes a processor 505. Although a single processor 505 is illustrated in Figure 3, two or more processors 505 may be used depending on the specific needs, requirements, or implementation of the computer 502 and the functions described. Generally, the processor 505 can execute instructions and manipulate data to perform operations of the computer 502, including operations using algorithms, methods, functions, processes, flows, and procedures as described in this disclosure.

[0041] Computer 502 also includes a database 506 that can hold data for Computer 502 and other components (whether shown or not) connected to the network 530. For example, database 506 can be an in-memory, conventional, or data-storing database consistent with the present disclosure. In some embodiments, database 506 can be a combination of two or more different database types (e.g., a hybrid in-memory and conventional database) depending on the specific needs, requirements, or implementation of Computer 502 and the functions described. Although shown as a single database 506 in Figure 3, two or more databases (of the same, different, or combination of types) can be used depending on the specific needs, requirements, or implementation of Computer 502 and the functions described. Although database 506 is shown as an internal component of Computer 502, in alternative embodiments, database 506 may also be external to Computer 502.

[0042] The computer 502 also includes a memory 507 that can hold data for the computer 502 or a combination of components connected to the network 530 (whether shown or not). The memory 507 can store any data consistent with the present disclosure. In some embodiments, the memory 507 may be a combination of two or more different types of memory (e.g., a combination of semiconductor and magnetic storage) depending on the specific needs, requirements, or implementation of the computer 502 and the functions described. Although the memory 507 is shown as a single memory 507, two or more memories 507 (of the same, different, or combination of types) may be used depending on the specific needs, requirements, or implementation of the computer 502 and the functions described. Although the memory 507 is shown as an internal component of the computer 502, in alternative embodiments the memory 507 may also be external to the computer 502.

[0043] Application 508 can be a software engine of algorithms that provides functionality according to the specific needs, requirements, or implementations of computer 502 and the functions described. For example, application 508 can function as one or more components, modules, or applications. Furthermore, although illustrated as a single application 508, application 508 can be implemented as multiple applications 508 on computer 502. Furthermore, although illustrated as being inside computer 502, in alternative embodiments application 508 may be outside computer 502.

[0044] The computer 502 may also include a power supply 514. The power supply 514 may include a rechargeable or non-rechargeable battery that can be configured to be either user-replaceable or non-user-replaceable. In some embodiments, the power supply 514 may include power conversion and management circuitry that includes recharge, standby, and power management functions. In some embodiments, the power supply 514 may include a power plug that allows the computer 502 to be plugged into a wall outlet or power source, for example, to supply power to the computer 502 or to recharge a rechargeable battery.

[0045] There may be any number of computers 502 that are associated with or external to the computer system including computer 502, with each computer 502 communicating via the network 530. Furthermore, the terms “client,” “user,” and other appropriate terms may be used interchangeably as appropriate without departing from the scope of this disclosure. Furthermore, this disclosure is intended to show that many users may use one computer 502, and that one user may use multiple computers 502.

[0046] The implementation of the subject matter and functional operations described herein may be carried out in digital electronic circuits, in tangibly embodied computer software or firmware, in computer hardware including the structures disclosed herein and their structural equivalents, or in one or more combinations thereof. The implementation of the software of the subject matter described herein may be carried out as one or more computer programs. Each computer program may include one or more modules of computer program instructions encoded in a tangible, non-temporary, computer-readable computer storage medium for execution by a data processing device or for controlling the operation of a data processing device. Alternatively or additionally, program instructions may be encoded in / on artificially generated propagating signals. For example, the signals may be mechanically generated electrical, optical, or electromagnetic signals generated to encode information for transmission to a receiver device suitable for execution by a data processing device. The computer storage medium may be a machine-readable storage device, a machine-readable storage board, a random or serial access memory device, or a combination of computer storage media.

[0047] The terms “data processing device,” “computer,” and “electronic computer device” (or equivalents as understood by those skilled in the art) refer to data processing hardware. For example, a data processing device can encompass any type of device, apparatus, and machine for processing data, including, as an example, a programmable processor, a computer, or multiple processors or computers. The apparatus may also include, for example, a central processing unit (CPU), a field-programmable gate array (FPGA), or a dedicated logic circuit, including an application-specific integrated circuit (ASIC). In some embodiments, the data processing device or dedicated logic circuit (or a combination of the data processing device or dedicated logic circuit) may be hardware-based or software-based (or a combination of both). The apparatus may optionally include code that creates an execution environment for computer programs, such as processor firmware, a protocol stack, a database management system, an operating system, or code that constitutes a combination of the execution environment. This disclosure intends to describe the use of a data processing device with or without a conventional operating system, such as LINUX, UNIX, WINDOWS, MACOS, ANDROID, or IOS.

[0048] Computer programs, which can also be referred to or described as programs, software, software applications, modules, software modules, scripts, or code, can be written in any form of programming language. Programming languages ​​can include, for example, compiled languages, interpreted languages, declarative languages, or procedural languages. Programs can be deployed in any form, including as standalone programs, modules, components, subroutines, or units used in a computing environment. Computer programs can, but are not required, correspond to files in a file system. Programs can be stored in part of files that hold other programs or data, such as, for example, a markup language document, a single file dedicated to the program, or one or more scripts stored in multiple collaborative files that store one or more modules, subprograms, or parts of code. Computer programs can be deployed to run on one computer, or to run on multiple computers, for example, located at one site or distributed across multiple sites interconnected by a communication network. While parts of a program shown in various diagrams may be represented as individual modules that perform various configurations and functions through various objects, methods, or processes, a program can instead include several submodules, third-party services, components, and libraries. Conversely, the configurations and functions of various components can be combined into a single component as appropriate. Thresholds used for computational decisions can be determined statically, dynamically, or both statically and dynamically.

[0049] The methods, processes, or logic flows described herein can be executed by one or more programmable computers that run one or more computer programs to perform a function by acting on input data and producing an output. The methods, processes, or logic flows can also be executed by dedicated logic circuits, such as a CPU, FPGA, or ASIC, and the apparatus can also be implemented as a dedicated logic circuit.

[0050] A computer suitable for running computer programs can be based on one or more general-purpose and dedicated microprocessors and other types of CPUs. The elements of a computer are the CPU for executing or achieving instructions, and one or more memory devices for storing instructions and data. Generally, the CPU can receive instructions and data from (and write data to) memory. A computer can also include, or be operationally coupled to, one or more mass storage devices for storing data. In some embodiments, a computer can receive data from and transfer data to mass storage devices, including, for example, magnetic disks, magneto-optical disks, or optical disks. Furthermore, a computer can be incorporated into another device, such as a portable storage device, such as a mobile phone, personal digital assistant (PDA), mobile audio or video player, game console, Global Positioning System (GPS) receiver, or Universal Serial Bus (USB) flash drive.

[0051] Computer-readable media (temporary or non-temporary, as appropriate) suitable for storing computer program instructions and data can include all forms of permanent / non-permanent and volatile / non-volatile memory, media, and memory devices. Computer-readable media can include semiconductor memory devices such as random access memory (RAM), read-only memory (ROM), phase-change memory (PRAM), static random access memory (SRAM), dynamic random access memory (DRAM), erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), and flash memory devices. Computer-readable media can also include magnetic devices such as tapes, cartridges, cassettes, and internal / removable disks. Computer-readable media can also include magneto-optical disks and optical memory devices, as well as technologies such as digital video discs (DVD), CD-ROM, DVD+ / -R, DVD-RAM, DVD-ROM, HD-DVD, and Blu-ray. Memory can store a variety of objects or data, including caches, classes, frameworks, applications, modules, backup data, jobs, web pages, web page templates, data structures, database tables, repositories, and dynamic information. The types of objects and data stored in memory can include parameters, variables, algorithms, instructions, rules, constraints, and references. Furthermore, memory can contain logs, policies, security or access data, and report files. The processor and memory can be supplemented by or integrated into dedicated logic circuits.

[0052] The implementation of the subject matter described herein can be carried out on a computer having a display device for providing user interaction, including displaying information to the user (and receiving input from the user). Types of display devices may include, for example, cathode ray tubes (CRTs), liquid crystal displays (LCDs), light-emitting diodes (LEDs), and plasma monitors. Display devices may include keyboards and pointing devices, including, for example, mice, trackballs, or trackpads. User input may also be provided to the computer through the use of a touchscreen, such as a pressure-sensitive tablet computer surface or a multi-touch screen using capacitive or electrical sensing. Other types of devices may be used to provide user interaction, including receiving user feedback, including sensory feedback, such as visual, auditory, or tactile feedback. User input may be received in the form of acoustic, voice, or tactile input. Furthermore, the computer may interact with the user by sending documents to and receiving documents from devices used by the user. For example, the computer may send a web page to a web browser on a user's client device in response to a request received from a web browser.

[0053] The term "graphical user interface," or "GUI," can be used in the singular or plural form to describe one or more graphical user interfaces and each display of a particular graphical user interface. Therefore, a GUI can represent any graphical user interface that processes information and efficiently presents the results of that information to the user, including, but not limited to, web browsers, touchscreens, or command-line interfaces (CLIs). Generally, a GUI can contain multiple user interface (UI) elements, some or all of which are related to web browsers, such as interactive fields, drop-down lists, and buttons. These and other UI elements may be related to or represent the functionality of a web browser.

[0054] The implementation of the subject matter described in this specification can be carried out in a computing system, which may include backend components, such as a data server, or middleware components, such as an application server. Furthermore, the computing system may include frontend components, such as a client computer, which may have either or both a graphical user interface or a web browser, from which a user can interact with the computer. The components of the system may be interconnected by any form or medium of wired or wireless digital data communication (or a combination of data communication) over a communication network. Examples of communication networks include local area networks (LANs), wireless access networks (RANs), metropolitan area networks (MANs), wide area networks (WANs), WiMAX (Worldwide Interoperability for Microwave Access), wireless local area networks (WLANs) (e.g., using 802.11a / b / g / n or 802.20 or a combination of protocols), all or part of the Internet, or any other one or more communication systems (or combinations of communication networks) in one or more locations. A network can communicate with, for example, Internet Protocol (IP) packets, Frame Relay frames, Asynchronous Transfer Mode (ATM) cells, voice, video, data, or a combination of communication types between network addresses.

[0055] A computing system can include clients and servers. Clients and servers can generally be located geographically separated from each other and typically interact via a communication network. The relationship between a client and a server can arise from computer programs running on each computer that have a client-server relationship.

[0056] A cluster file system can be any file system type that is accessible from multiple servers for reading and updating. Locking of the exchange file system can be done at the application layer, so locking or consistency tracking may not be necessary. Furthermore, Unicode data files can be different from non-Unicode data files.

[0057] This specification includes many specific details of the implementation, but these should not be construed as limitations on the scope of what can be claimed, but rather as descriptions of configurations that may be specific to a particular implementation. Certain configurations described herein in the context of separate implementations may also be implemented in combination in a single implementation. Conversely, various configurations described in the context of a single implementation may also be implemented separately or in any appropriate subcombination in multiple implementations. Furthermore, the aforementioned configurations may be described as operating in a particular combination and may be initially claimed as such, but one or more configurations from the claimed combination may, in some cases, be removed from that combination, and the claimed combination may cover subcombinations or variations of subcombinations.

[0058] Specific embodiments of the subject matter have been described. Other implementations, modifications, and substitutions of the described implementations are within the following claims, as will be apparent to those skilled in the art. Although the operations are shown in a particular order in the drawings or claims, this should not be understood as requiring that such operations be performed in a particular order or sequence shown in order to achieve a desired result, or as requiring that all illustrated operations be performed (some operations may be considered optional). In certain circumstances, multitasking or parallel processing (or a combination of multitasking and parallel processing) is performed where it is advantageous and appropriate.

[0059] Furthermore, the separation or integration of various system modules and components in the implementations described above should not be understood as requiring such separation or integration in all implementations. It should also be understood that the described program components and systems can generally be integrated into a single software product or packaged into multiple software products.

[0060] Therefore, the exemplary embodiments described above do not define or limit the disclosure. Other modifications, substitutions, and alterations are also possible without departing from the spirit and scope of the disclosure.

[0061] Furthermore, any requested implementation is considered applicable to at least a method performed by a computer; a non-temporary computer-readable medium storing computer-readable instructions for performing the method performed by a computer; and a computer system. The computer system includes computer memory operably coupled to hardware processors, and the hardware processors are configured to execute the methods or instructions performed by a computer stored in the non-temporary computer-readable medium.

[0062] Multiple embodiments of these systems and methods have been described. However, these systems and methods may include other embodiments. For example, although the systems and methods were described in the context of a bioreactor, the described systems and methods may be useful in other contexts as well. This type of control is similar to a hybrid of a model predictive controller and a PID controller. It can be applied to increase the robustness of the control by utilizing the output of the PID controller and determining its relationship or correlation with other measurements in the bioreactor. This type of control scheme can be used when there is excessive noise in the input measurements that affects the output of the PID controller. By extending the PID controller with a model, the output of that controller can be made more reliable. This can be done by replacing the direct output of the PID with the expected output of the model, or by imposing constraints on the PID through the expected output from the model. In this example, oxygen control using capacitance measurements is demonstrated (a first in the industry).

Claims

1. It is a system: One or more sensors configured to capture measurement data representing dissolved oxygen (DO) measurements of the bioreactor and capacitance measurements of the bioreactor's medium; Computer-readable memory containing computer-executable instructions; One or more processors, which are communicatively coupled to one or more sensors and configured to execute computer executable instructions, Including, when one or more processors are executing computer executable instructions, the one or more processors: Using first measurement data acquired by one or more sensors during a first time interval, representing a first set of DO measurements and a first set of capacitance measurements, a model is generated that represents the slope between oxygen output and capacitance based on the relationship between the first set of DO measurements and the first set of capacitance measurements; Receiving from one or more sensors, second measurement data representing new DO measurements and new capacitance measurements captured by the one or more sensors during a second time interval; Applying the model to the new capacitance measurement to generate the expected DO measurement; To determine the oxygen input, it is necessary to decide whether to use the expected DO measurement or a new DO measurement; When it is decided to use the expected DO measurement value, the valve is controlled to flow the determined oxygen input amount into the bioreactor based on the expected DO measurement value. The system is configured to perform operations including the following.

2. The decision of whether to use the expected DO measurement or a new DO measurement is: Determining the rate of change of DO based on new DO measurements and a first set of DO measurements; Determining the rate of change of capacitance based on new capacitance measurements and a first set of capacitance measurements; When the rate of change of DO exceeds the rate of change of capacitance by a threshold, it is decided to use the expected DO measurement. The system according to claim 1, including the following:

3. The system according to claim 1, further comprising a bioreactor, wherein one or more sensors include a DO sensor and a capacitive sensor.

4. The decision of whether to use the expected DO measurement or a new DO measurement is: Comparing new capacitance measurements with capacitance thresholds; When a new capacitance measurement exceeds the capacitance threshold, it is decided to use the new DO measurement. The system according to claim 1, including the following:

5. The decision of whether to use the expected DO measurement or a new DO measurement is: To compare the expected DO measurement with the new DO measurement; When the expected DO measurement exceeds the new DO measurement, it is decided to use the expected DO measurement. The system according to claim 1, including the following:

6. The operation is: Receiving from one or more sensors, during a third time interval, third measurement data representing a second set of DO measurements and a second set of capacitance measurements, captured by the one or more sensors; The model is updated based on the third set of measurement data, The system according to any one of claims 1 to 5, further comprising:

7. The system according to claim 6, wherein the third measurement data includes the second measurement data.

8. A method for controlling oxygen levels in a bioreactor: A model is generated representing the slope between oxygen output and capacitance based on the relationship between the first set of DO measurements and the first set of capacitance measurements, using first measurement data acquired by one or more sensors during a first time interval, which represent a first set of DO measurements and a first set of capacitance measurements, wherein one or more sensors are configured to acquire measurement data representing dissolved oxygen (DO) measurements of the bioreactor and capacitance measurements of the bioreactor medium; Receiving from one or more sensors, second measurement data representing new DO measurements and new capacitance measurements captured by the one or more sensors during a second time interval; Applying the model to the new capacitance measurement to generate the expected DO measurement; To determine the oxygen input, it is necessary to decide whether to use the expected DO measurement or a new DO measurement; When it is decided to use the expected DO measurement value, the valve is controlled to flow the determined oxygen input amount into the bioreactor based on the expected DO measurement value. The method, including the method described above.

9. The decision of whether to use the expected DO measurement or a new DO measurement is: The rate of change of DO is determined based on the new DO measurement and the first set of DO measurement values. Toto; Determining the rate of change of capacitance based on new capacitance measurements and a first set of capacitance measurements; When the rate of change of DO exceeds the rate of change of capacitance by a threshold, it is decided to use the expected DO measurement. The method according to claim 8, including the method described in claim 8.

10. The method according to claim 8, wherein one or more sensors include a DO sensor and a capacitance sensor.

11. The decision of whether to use the expected DO measurement or a new DO measurement is: Comparing new capacitance measurements with capacitance thresholds; When a new capacitance measurement exceeds the capacitance threshold, it is decided to use the new DO measurement. The method according to claim 8.

12. The decision of whether to use the expected DO measurement or a new DO measurement is: To compare the expected DO measurement with the new DO measurement; When the expected DO measurement exceeds the new DO measurement, it is decided to use the expected DO measurement. The method according to claim 8, including the method described in claim 8.

13. Receiving from one or more sensors, during a third time interval, third measurement data representing a second set of DO measurements and a second set of capacitance measurements, captured by the one or more sensors; The model is updated based on the third set of measurement data, The method according to any one of claims 8 to 12, further comprising:

14. The method according to claim 13, wherein the third measurement data includes the second measurement data.

15. A non-temporary computer-readable medium for storing instructions, wherein when an instruction is executed by one or more processors, it is stored in that one or more processors: A model is generated representing the slope between oxygen output and capacitance based on the relationship between the first set of DO measurements and the first set of capacitance measurements, using first measurement data acquired by one or more sensors during a first time interval, which represent a first set of DO measurements and a first set of capacitance measurements, wherein one or more sensors are configured to acquire measurement data representing dissolved oxygen (DO) measurements of the bioreactor and capacitance measurements of the bioreactor medium; Receiving from one or more sensors, second measurement data representing new DO measurements and new capacitance measurements captured by the one or more sensors during a second time interval; Applying the model to the new capacitance measurement to generate the expected DO measurement; To determine the oxygen input, it is necessary to decide whether to use the expected DO measurement or a new DO measurement; When it is decided to use the expected DO measurement value, the valve is controlled to flow the determined oxygen input amount into the bioreactor based on the expected DO measurement value. The non-temporary computer-readable medium that causes the operation including the execution of the operation.

16. The decision of whether to use the expected DO measurement or a new DO measurement is: Determining the rate of change of DO based on new DO measurements and a first set of DO measurements; Determining the rate of change of capacitance based on new capacitance measurements and a first set of capacitance measurements; When the rate of change of DO exceeds the rate of change of capacitance by a threshold, it is decided to use the expected DO measurement. A non-temporary computer-readable medium according to claim 15, including the following:

17. The non-temporary computer-readable medium according to claim 15, wherein one or more sensors include a DO sensor and a capacitance sensor.

18. The decision of whether to use the expected DO measurement or a new DO measurement is: Comparing new capacitance measurements with capacitance thresholds; When a new capacitance measurement exceeds the capacitance threshold, it is decided to use the new DO measurement. A non-temporary computer-readable medium according to claim 15, including the following:

19. The decision of whether to use the expected DO measurement or a new DO measurement is: To compare the expected DO measurement with the new DO measurement; When the expected DO measurement exceeds the new DO measurement, it is decided to use the expected DO measurement. A non-temporary computer-readable medium according to claim 15, including the following:

20. The operation is: Receiving from one or more sensors, during a third time interval, third measurement data representing a second set of DO measurements and a second set of capacitance measurements, captured by the one or more sensors; The model is updated based on the third set of measurement data, A non-temporary computer-readable medium according to any one of claims 15 to 19, including the following:

21. The non-temporary computer-readable medium according to claim 20, wherein the third measurement data includes the second measurement data.

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