© TAP BIOSYSTEMSLet’s face it: cell culture is tedious work. Researchers sit straight-backed with arms extended inside a laminar-flow hood. It’s usually loud and warm, and if you do a lot of it, your back and arms will ache—all of which can challenge your precision and efficiency.
These drawbacks, coupled with the nature of the job, make cell culture well-suited for automation, which offers higher accuracy and reproducibility than manual cell culture, plus a lower risk of error and contamination. Automation “brings a great deal of standardization to a process that can be quite variable if done by hand,” says Scott Noggle, lab director at the nonprofit New York Stem Cell Foundation, which has a custom-built Hamilton robotic system automating most of its culture workflow. Off-the-shelf solutions exist as well (see “Set It and Forget It,” The Scientist, March 2013).
But these high-end systems can cost $1 million or more, putting them out of the reach of most academic and core lab facilities. Other platforms, however, automate various individual steps of the cell-culture workflow. These relatively modest instruments (many can be had for under $100,000) don’t do everything, but they can ease the pain of some fairly mind-numbing tasks and free researchers to focus on what they were trained to do: design and execute experiments.
Here, The Scientist highlights five automation tools for the more budget-conscious cell-culture practitioner.
Fill-It | TAP Biosystems
What it does: The TAP Biosystems Fill-It automates the process of uncapping, filling, and recapping cryovials prior to cell freezing—a workflow that can quickly grow old for staff at facilities such as microbial strain banks and mammalian cell banks. Fill-It can process a single rack of 96 tubes in under 135 seconds, says product manager Stephen Guy. That speed is important because once cells are exposed to cryopreservative, they must be frozen quickly to retain viability.
According to Guy, Fill-It makes the most sense for labs that prepare more than 300 or so vials at one sitting, and especially those that must do so under GMP (good manufacturing practice) conditions. For fewer vials, Guy recommends pipetting cells manually and using an automated capping/decapping system, such as the Thermo Scientific Capit-All, also manufactured by TAP. Alex Hiscott, ECACC cell banking unit manager at the Culture Collections of Public Health England, uses Fill-It for batches larger than 100 vials; a 24-tube rack can be filled in under a minute. “It gives the advantage that ampules are filled uniformly and quite quickly,” he says.
Pros: Fill-It can accommodate cryovials from a range of vendors, including Thermo Fisher, Corning, and Greiner Bio-One. “We have Fill-It systems that are compatible with the different manufacturers’ tubes, but we don’t have one Fill-It that actually is compatible with all the different tubes.” That’s because each tube is a different size and shape and requires, for instance, different torques for capping and uncapping, Guy explains.
Key to Fill-It’s aseptic operation is a disposable “tube set,” Guy says, a sterile piece of plastic tubing with nozzles on one end. Users place one end into their cell mixture and attach the nozzle end to the Fill-It. After dispensing, the tubing is discarded.
A GMP-compliant version of the system is also available.
Cons: At 44 kg, the Fill-It is too heavy to be moved in and out of a laminar flow hood by just one person. Hiscott says his facility ordered custom hoods with a reinforced work surface to accommodate the extra load. He recommends checking with your hood’s manufacturer to determine whether that’s necessary. “It’s not an issue as long as you think ahead.”
Extras: To help with this challenge, TAP sells a “mini-stacker trolley” to raise the Fill-It to hood height, install it in the hood, and remove it afterwards. When not in use, the Fill-It can be stored on the trolley in an out-of-the-way corner of the lab.
Cost: Around $80,000
epMotion 5070 CB | EPPENDORF
What it does: epMotion is Eppendorf’s brand name for robotic workstations, with systems for everything from nucleic-acid extraction to PCR setup. The 5070 CB targets the cell-culture environment.
“The CB refers to ‘clean bench,’” explains product manager Jesse Cassidy. “It’s intended to be inserted into a laminar-flow hood.” The lowered sash on the hood serves as the enclosure for the system, which is otherwise open to the air. The 5070 CB is “a piston-stroke, air-displacement system, which uses disposable, sterile filter tips to dispense volumes from 1 μL to 1 mL,” Cassidy says. Capable of such applications as cell seeding, serial dilutions, growth curves, and bioassays, “the system can do anything you can do on the bench with a pipette.” That includes the emerging application of 3-D cell culture using the 3D Biomatrix Perfecta3D hanging-drop system.
Pros: “The epMotion has unmatched precision at low volume,” Cassidy says, adding that researchers can achieve performance in small-volume liquid handling that is superior to what they could attain manually.
Jeremy Nelson, a senior research professional at Allergan who uses the 5070 CB to prepare sterile serial dilutions, says the instrument saves him 1–2 hours of hands-on time each week. But the biggest plus, he says, is uniformity. “You’re eliminating human variability in this one aspect of the experiment.”
The system is also vendor-agnostic, so users aren’t locked into a particular brand or consumable supplier (except for tips, which must be purchased from Eppendorf “for accuracy and performance reasons,” Cassidy says).
Another perk: It’s equipped with an optical-sensor system, which ensures that the work environment is clean; that vessels and tips are on deck and properly positioned; and that there’s enough reagent available to perform the requested workflow.
Cons: The 5070 CB is intended for use with microtiter plates, but manual intervention is required for lid removal. The system is limited to four on-deck and three off-deck positions for microplates, and some larger vessels, including T flasks, are not compatible.
Extras: Popular accessories include new liquid-handling heads (single and 8-channel manifolds, for instance) and racks to accommodate tubes such as Eppendorf microfuge tubes, cryovials, and reagent reservoirs.
Cost: Starting under $35,000
Info: www.eppendorf.com/int/index.php?action=products& catalognode=61122
XTL-96 | FluidX
ROBIN GRIMWOOD/FLUIDXWhat it does: The XTL-96 is an automated tube labeler, capable of printing and attaching adhesive labels to 800 tubes per hour. According to Robin Grimwood, codirector and cofounder of FluidX, the XTL-96 is intended for labs, biobanks, core facilities, and reagent repositories—any place that needs to supply large numbers of labeled tubes.
Pros: The advantage of the XTL-96 isn’t really speed, Grimwood says—anyone can pull together a bunch of grad students for a marathon tube-labeling session—but consistency. Users applying manual labels inevitably attach them at different positions on the tube each time, which can, for instance, cause them to get stuck in racks or be misaligned in a barcode reader.
Furthermore, well-labeled (and barcoded) tubes allow labs to extend the life of their archived samples, by making them more easily identified. “You can read your own writing. But when you leave [the lab], what happens then?” he says.
Cons: Price. Some users may balk at spending tens of thousands on a Sharpie alternative. In that case, Grimwood recommends FluidX’s “jacket tubes,” prelabeled cryotubes containing a 2-D barcode on the bottom and a linear bar-code and human-readable tube identifier (supplied by FluidX) laser-cut into the side. “If all you want is a way of tracking an individual sample, then a jacket tube can have that as standard,” he says. Jacket tubes cost 15 percent above standard 2-D barcoded tubes, Grimwood says.
Extras: The standard XTL-96 can accommodate one rack, but a four-rack version is also available. Also, systems come customized for particular tube formats and sizes. The tube format can be changed, but it requires a new rack, as well as reprogrammed “grippers” for holding and rotating the tubes.
Cost: $60,000–$70,000, depending on configuration
ClonaCell EasyPick | STEMCELL Technologies & Hamilton Robotics
What it does: The ClonaCell EasyPick automates cell colony isolation from semisolid (as opposed to liquid) growth medium.
Used to isolate, for instance, libraries of individual hybridoma colonies, the ClonaCell EasyPick performs more than 200 colony isolations per hour, selecting clones based on user-defined morphology parameters and placing them in liquid media for expansion and testing.
According to STEMCELL Technologies’ product marketing manager, Jenna Moccia, the ClonaCell EasyPick is used mostly by biopharmaceutical companies, contract research organizations, and contract manufacturing organizations—facilities that need to isolate and test large numbers of clones for protein or antibody development. Academic hybridoma facilities and the like might also benefit.
Pros: Moccia says the labor and time savings afforded by the ClonaCell EasyPick can be “incredibly valuable,” because it takes considerable time and patience to pick clones one by one. But there are other benefits, too. Users can specify clone size and shape, for instance, to avoid “oblong” clones that really are two colonies close together. The instrument’s throughput means users can collect and test more clones than they might otherwise, giving them a better shot at finding cultures with the desired characteristics and increasing library diversity. And the machine can do so with lower risk of contamination than even a skilled technician could manage.
Cons: Given the cost of the system, the ClonaCell EasyPick really only makes sense for industrial labs and high-volume academic facilities. The sad fact is, the low cost of graduate-student and technician time rarely justifies the expense of such a system, Moccia says.
Extras: The ClonaCell EasyPick is available in an extended-deck configuration for integration with upstream and downstream automation. For instance, users can add an ELISA screening module to test clone protein output and activity following isolation.
Cost: Approximately $175,000–$350,000,
depending on configuration
EVOS FL Auto | Life Technologies
LIFE TECHNOLOGIESWhat it does: Life Technologies’ EVOS FL Auto is a hands-free, fluorescence, brightfield, and phase-contrast microscope that automates the process of time-lapse imaging. Users tell the instrument where to image and at what interval, and the FL Auto does the rest.
Pros: Setting up time-lapse experiments can require expertise, as well as high-end microscopes with third-party add-ons. The software systems can be complex, and the microscopes often cannot be used without extensive training. The EVOS FL Auto, though, with its simple touch-screen interface, is relatively easy for even novices to use, says Hans Beernink, imaging product management leader at Life Technologies.
Also, whereas fluorescence microscopes are generally kept in darkrooms, the FL Auto is a benchtop instrument that can be housed anywhere. “It can be done in the tissue-culture lab, which is highly preferable for folks who are working with cells quite frequently,” Beernink says. “You’d like to keep the cells within that sterile environment.”
Jarkko Ylanko, a research technician at the Sunnybrook Research Institute in Toronto, helped buy an FL Auto for his lab. The lab already has a dedicated system for time-lapse imaging, but the FL Auto, he says, “is just so easy to drive,” which translates into increased use. “In the coming years, I think this is going to be a very popular microscope,” Ylanko says.
Cons: The FL Auto is neither a confocal instrument nor a high-throughput imager. Whereas some high-content screening systems can take 40 images per second (albeit generally on fixed cells), the FL Auto takes only five. Thus, it can capture relatively slow processes, like cell migration and morphology changes, but not, say, fast signaling events. “Our instrument is really designed to be able to take successive images over multiwell plates, but not at a speed that allows you to do [very fast] real-time biology,” Beernink says. The instrument also does not include plate hotels and a plate autoloader, so user intervention is required to change samples unless additional equipment is acquired.
Extras: The system accommodates different “stage inserts” to hold, for instance, multiwell plates, T flasks, petri dishes, or slides. A stage-top incubator is available for extended imaging in an environment with controlled temperature, humidity, and gas conditions.
Cost: The base unit costs $50,000, plus light cubes, filters, and objectives. The onstage incubator adds $14,200. The “all-out” cost is under $75,000, Beernink says.