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Bioreactors and Fermentors
Buying Tips
Apr 3 '08
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Introduction |
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| Perhaps you’re tired of the daily tasks that cell culture entails, or perhaps you’re looking to scale up to larger cell culture volumes, and plastic dishes and tiny wells are no longer feasible. Perhaps it’s a good time to consider a bioreactor – or for yeast and bacterial cultures, a fermentor – for your next set of experiments. Generally, a bioreactor is a vessel in which a batch of cells is grown under controlled conditions.
Bioreactors and fermentors have come a long way since the difficult-to-clean metal vats that were stirred from the bottom to mix (and poorly aerate) the contents. They are now available in a range of volumes, a variety of physical structures, and degrees of automation, examples of which will be discussed here. But ultimately, all makers of bioreactors and fermentors share the goal of caring for your cells as you would. “A major challenge for all bioreactor manufacturers is to support all the process parameters [for] the successful cultivation of the growing number of cell lines needed by customers,” says Jarno Mäkinen, vice president of product development at Medicel. “Dynamic control of agitation, aeration, gas mixing, temperature, pH and dissolved oxygen are supported to accommodate the diverse cell lines.” |
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Mini and modular designs |
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| Embracing a wide range of applications is New Brunswick Scientific, which manufactures bench to production-scale cell culture bioreactors and microbial fermentors for applications ranging from biofuels research to production of proteins and vaccines. The company offers a low-cost, labor-saving 500 mL disposable cell culture system, as well as traditional stirred-tank bioreactors in 1– 650 L capacities, and fermentors that range from 1 – 3000 L. New products include the sterilizable-in-place 19.5 and 40 L BioFlo 510™ fermentors and CelliGen 510™ bioreactors. “System flexibility is the key advantage that makes the 510 systems unique,” says Suzy Kedzierski, New Brunswick Scientific’s marketing communications manager. “Their modular design makes it easy for our customers to add or remove system components at any time, pre- or post-delivery, to accommodate changes in process requirements. We've added numerous ports in the vessel headplate and sidewall to provide the flexibility to position probes, spray balls, addition valves, pressure transducer and more, exactly where needed. Multiple analog inputs and outputs are provided for integrating up to 14 external devices for optimizing process control, [and] we offer multiple options for gas flow control, validation packages, redundant probes and more, for customizing the system to user requirements.”
For a mini bioreactor (0.1 – 1 ml) that can evolve into a system with much larger capacities, consider DASGIP’s new BioLector system, which uses 48- and 96-well plates contained within a controlled unit. Jennefer Vogt, of DASGIP’s marketing and communications, says that “the BioLector monitors cell growth and protein production in up to 96 wells online and in parallel. Additionally, pH or dissolved oxygen can be monitored in each well.” Working with smaller volumes and standard plates compatible with robotic systems can facilitate screening studies, after which candidates can be selected and studied using DASGIP’s parallel bioreactor system, cellferm-pro, which can incorporate up to 16 parallel reactors of larger capacities. Cellferm-pro is a modular system designed to be cost-efficient, flexible, and space efficient. |
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Fermentors and alternative biofuels |
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| DASGIP’s parallel systems can also be configured for use as fermentors. The evolution of fermentors in general may experience a quickened pace in the near future, as vessels of potential oil alternatives. “Certainly biofuels as an alternative energy source is both an emerging technology that’s timely and well funded today,” says Kedzierski. DASGIP’s Vogt agrees: “From my point of view, biofuel development ...[is one of] the most exciting applications in the near future. In biofuels development, new organisms and processes have to be developed to make it a real alternative to oil. Therefore, bioprocess equipment needs to provide anaerobic conditions, high temperature tolerances, and integration of multi-step processes (from pre-treatment to (m)ethanol production).” Vogt explains that this will entail tight control and monitoring of many parameters, some of which may still be unknown. “DASGIP has geared its line of parallel bioreactor systems towards the needs for biofuel development, providing monitoring and control of pH and redox potential, gas supply of non-common gasses such as methane, and temperature control up to 95°C,” says Vogt. “Multi-step processes and operation in up to 16 vessels can be integrated into one system.”
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Bioreactors with unconventional forms |
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| Two other types of bioreactors are less conventional in form, yet pack a punch when it comes to production . One is hollow fiber cell culture, offered by FiberCell Systems. Hollow fiber cell culture is modeled after the mammalian circulatory system: media flows through small hollow tubes made from a porous material, upon which cells grow. Nutrients are delivered to the cells via the tubes, and cells secrete products into the media, which flows into the tubes for eventual collection. Hollow fiber cell culture is typically used to produce monoclonal antibodies, recombinant proteins, or adenoviral vectors, for example. It is also used for cytokine and growth factor production, and lymphocyte expansion. The culture system can be used for different purposes depending upon which type of hollow fiber cartridge is used (cartridges contain types of fibers specific for certain applications). FiberCell Systems has several new cartridges on offer. The first, intended for stem cell research, “allows the attachment of different matrices, cytokines and antibodies to the surface of the hollow fiber for long term growth and differentiation studies,” says John Cadwell, FiberCell Systems’ president and CEO. The second cartridge maximizes monoclonal antibody production to 20-100 mg per harvest.
The third new cartridge is a medium supplement to replace serum, optimized for the unique, high cell density found in hollow fiber bioreactors. “Potential scale-up for production of protein-based therapeutics remains an issue,” says Cadwell. “Related to that is the expense of downstream processing of dilute products. Hollow fiber allows for the culture of cells at high cell densities, simplifying medium requirements. Hollow fiber can also produce proteins at a concentration of 100X or higher vs. conventional cell culture. In the past, hollow fiber systems have not been scalable. FiberCell Systems is developing the first truly scalable hollow fiber bioreactor system.” Cadwell believes that the co-evolution of media and bioreactors that are designed to work together will serve to increase production of cell-based products in the future.
Another unconventional bioreactor takes the form of a plastic bag – high-tech plastic, that is. Wave Biotech, now part of GE Healthcare, developed disposable cell culture systems for 0.1 - 500 L capacities based on their Cellbag – a presterilized plastic bag with filters, tubes, and fittings – and a rocker unit. The Cellbag is designed to lie flat, partially full of media, on the rocker unit’s platform; the rocking motion produces waves in the culture fluid that encourage mixing and oxygen transfer. There are options for dissolved oxygen monitoring, and controls for carbon dioxide, temperature, weight, and pH. Because the Cellbag is a completely closed system, it is ideal for virus or vaccine production or other high containment applications. Truly disposable, you simply place a new bag on the rocker, fill it with media, and add your cells. Four different systems are available depending on your desired scale of production. |
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Automation with multiple bioreactors |
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| For the ultimate hands-free cell culture experience, you might consider Medicel’s Explorer system, whose core is a cell cultivation unit with 15 parallel bioreactors (100 – 500 ml volumes). The system provides individual controls for each bioreactor for agitation, temperature, aeration, pH, dissolved oxygen, and feeding. “Due to its broad functionality and high degree of automation, Medicel Explorer supports the planning and execution of complex experiments at different stages of the traditional bioprocess development,” says Mäkinen. “They include screening of cell strains for product yields, optimization of growth conditions for the selected strain, and scale up of the manufacturing process.” Mäkinen adds that Explorer’s functional integration and automation “allow the planning and execution of large and complex cell cultivation experiments with high precision and minimum amount of labor.”
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Homes for stem cells |
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| Will complete automation be the future for bioreactors, which have already relieved many scientists of the daily rituals of pipetting into plastic culture dishes? Perhaps, but therapeutics might be a more likely development in the near future. Vogt believes that regenerative medicine is another exciting application of bioreactors. “In stem cell research, it is crucial to produce cell numbers required for clinical studies – and to produce them in reproducible quality,” says Vogt. Mäkinen also sees an important future for stem cells in bioreactors. “The number of different cell lines cultivated in bioreactors is growing and moving towards mammalian cell lines, including human cell lines,” says Mäkinen. “The use of these cell lines as production hosts will eventually grow, particularly in the production of post-translationally decorated protein drugs. It is also highly probable that stem cell lines will be grown in bioreactors under well-controlled growth conditions some time in the future.” But Cadwell cautions that there is still a long way to go. “I believe that the interactions between matrices and solid phase bound cytokines and stem cells havee not yet begun to be explored,” he says. “This is unexplored territory and requires the use of porous supports and perfusion for long term culture. The use of bioreactors to expand stem cells and other defined cell and tissue types is in its infancy.”
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Caitlin Smith
Contributing Writer
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