Monitoring and control of bioreactors

Kilburn J (1991), Monitoring and control of bioreactors, In Mammalian Cell Biotechnology A Practical Approach, Butler M (Ed.), Oxford University Press, New York, pp. 159-184. 

Stem Cell Isolation and Initial Characterization Bioprocess Development and Optimization Based on Microscale High-Throughput Profiling Monitoring and Control of Bioreactor... 

Commercial scale cultivation of mammalian cells is accompHshed using different technologies roller bottles, microcarriers, suspension (batch, fed-batch or perfusion mode) and hollow fiber bioreactors (Table 2). However, especially for products needed in large amounts, suspension cultivation seems to be the most effective system [4, 5]. Suspension-based systems are characterized by a homogeneous concentration of cells, nutrients, metabolites and product, thereby facilitating scale-up [6] and enabling an accurate monitoring and control of the culture [7]. 

Work with these types of electrodes enables to achieve steady-state current conditions within a short time-period. Primarily proposed for monitoring and control of blood and tissue oxygen tension [10], the electrode systems with selective membranes were manufactured and used in continuous oxygen measurement in a wide variety of aqueous solutions [11]. The sensors of this type, called Clark electrodes, are described in chapter 6 of this volume. Improvements designed for continuous monitoring in industrial bioreactors may be found in section 6 of chapter 3. The most important feature of the membranes used in these sensors is their selectivity which prevents poisoning the electrode system and deteriorating the adherent electrolyte solution. 

In engineering terms, a sanitary landfill is also sometimes identified as a bioreactor due to the presence of anaerobic activities in the wastes. As such, landfilling sites need the incoming waste stream top be monitored, as well as placement and compaction of the waste, and installation of landfill environmental monitoring and control facilities. Gas vent and leachate collection pipes are important features of a modem landfill. 

In general, the subsequent stages occur in small bioreactors, known simply as flasks or bottles, since they have no monitoring and control system and are usually disposable. Apart from flasks and bottles, multiwell plates can be used to culture cells, but their use is restricted mainly to cloning and selection of cells. 

Whatever the scale or method of culture (T-flask, Schott bottle, spinner flask, or bioreactor), the temperature of the culture medium with which the cells are in contact is always a fundamental state variable, because it interferes with growth and the production process. However, it is a process variable that is easy to monitor and control. On a small scale the culture flask is usually put in a thermostatically controlled incubator, where the measured value of a thermometer sends a sign to turn the heating on or off ( on-off control ). In bioreactors, there are equivalent systems, as will be seen later. Usually, however, a resistance thermometer sensor type is used (resistance temperature detector or RTD), the electric... 

In addition to this technical oriented development, a broad field of applied biological research was at the center of interest in Fiechter s laboratory. The development of bioreactors, bioprocess monitoring and control served as a means of obtaining more information on the biology of microorganisms and improving the process performance. 

The measurement of analyte concentration is a critical part of successful bioreactor monitoring. Although strategies exist for measuring the majority of relevant analytes, industrial online bioreactor control is carried out primarily by measurement and control of temperature, pH, d02, CO2, and, in some cases, cell density. This is because the available technology cannot be easily and inexpensively adapted to measure the analyte in an aseptic manner and measurement is not often achieved in real time so that online control is challenging. Biosensors for a variety of applications for... 

One additional area that is on the horizon is the potential to optimize biologically based processes with microscale equipment. An approach developed by BioProces-sors is a Simcell platform, which is an automated miniaturized system for cell culture development. This platform is capable of running and monitoring hundreds of complex bio-reactions. This automated platform has been used to conduct high-throughput cell culture experiments for process development purposes. The system performs bioreactor operations such as cell inoculation and culture monitoring and control. 

The last step of a bioprocess based on plant cells or organ cultures is the scale-up to bioreactor level. In these processes, it is possible to monitor and control several parameters, including ... 

The experimental setup is shown in Figure 1. It comprises a cell recycle membrane bioreactor, measuring equipment and sensors, and an online monitoring and control system. The membrane reactor consists of a stirred vessel with an effective volume of 0.45 L, coupled to a membrane module. The contaminated water is pumped tangentially along the membrane surface with a cross-flow velocity of 1 m/s, generating two streams a permeate stream free of cells (treated water), and a retentate stream (with cells) which is... 

An example of a pulsatile-flow bioreactor for vascular grafts is shown in Figure 44.3. This design, used in the Laboratory of Cardiovascular Tissue Engineering at the University of Oklahoma, resembles the shell and tube concept of some heat exchangers. Flow circuits are separated into shell-side and tube-side to monitor (and control) system pressure and flow rates independently. Control valves downstream... 

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