Enablers of High-Throughput Assays
Automated liquid handlers encompass a range of instruments and systems whose function is to dispense liquids rapidly, usually in very small quantities, at user-specified volumes, and with great accuracy, precision, and reproducibility.
Liquid handlers are sold in a variety of fluid-dispensing configurations, from single-channel through eight (one row of a 96-well microtiter plate), 96, and 384 channels. As the successors to manual pipettes, automated liquid handlers are the principal enablers of rapid experiments and assays conducted in tubes, vials, or microtiter plates. Liquid handlers are often just one component of systems consisting of microplate handlers, washers, readers, stackers, shakers, and incubators. Automation became necessary as assays were miniaturized from vials to tubes, and finally to microplates, and as researchers switched from radionuclide-based assays to tests that used non-radioactive detection.
Biology, medical testing, and screening of development-stage drugs are the primary markets for automated liquid handling. The energy, environmental, and heavy industries also use liquid handlers when accuracy and reproducibility, but not necessarily high throughput, are desired. “Any time you work with many samples and small quantities of fluids, automating liquid handling with a workstation will provide good return on investment,” says Scott Eaton, director of robotics marketing at Hamilton (Reno, NV).
Assessing workflow requirements is essential when selecting an automation system. Liquid transfers take time, which adds up rapidly as dispensing and other operations increase. Users who work with labile or highly toxic samples or reagents may prefer to process a smaller number of plates per run in order to move them rapidly through the protocol.
Another factor to consider, Eaton says, is the effect of physical forces on very small liquid-dispensing volumes used in higherdensity plates. “While 96-well plates remain the most common, 384- and even 1,586- well systems that employ sub-microliter volumes are gaining in popularity. At these volumes, evaporation and absorption onto the plastic plate surface become issues.”
Automated liquid handlers have evolved from automated pipetting systems to workstations that employ liquid handling as one component, according to Nance Hall, vice president for automation and detection systems at PerkinElmer (Waltham, MA). Today’s systems perform washing, incubation, and plate manipulation in addition to dispensing. “In the past, liquid handlers performed just one function; today, they are ‘application solutions’ in which liquid handling is part of a larger picture,” Hall says.
Eaton believes a combination of ease-ofuse and flexibility in software is an important differentiator when selecting an automated liquid handler. “Some software is very easy to use, but it’s locked into specific applications.” The best of both worlds, he says, is a software package that presents operations graphically, provides “wizards” or templates for routine tasks, and that adapts to different assays.
Hall suggests that potential buyers analyze their liquid-handling needs the way a cook examines a recipe. “What are the ‘ingredients’? What labware are we dispensing from and into? What do I expect from the automation component? What volumes are involved, and what sample-tip options are available?” Hall says. “Users who fail to optimize the liquid handler’s fluidics design to desired volumes will be forced to compromise either on performance or throughput.”
Users should weigh throughput considerations when considering a liquid-handler purchase, says Jason Greene, liquid-handling product manager at BioTek (Winooski, VT). “The cutoff point for automation versus a multi-channel handheld pipette is several strips [rows or columns on a microplate] per day,” Greene says.
This seems like a small number of assays to justify the investment in automation, but as Greene notes, liquid handling is just one component of what may be a complex workflow. “Operating manually, users must work through the various reagent additions, incubations, washing, and reading steps,” he says. “Nobody likes to wash microplates. It’s pretty easy to get users to buy into the idea of automation on that function alone.” Moreover, he says, even low-throughput labs come to value the reproducibility of automated systems.
For Nadine Gassner, associate director of the Chemical Screening Center at the University of California-Santa Cruz, experience with a particular vendor is a major factor in selecting a liquid-handling system. The center, which performs highthroughput screening on natural-product and newly synthesized drug candidates, has the capability of testing hundreds of thousands of compounds in one experiment using 96- and 384-well plates.
Gassner had already been using a PerkinElmer plate reader. During the startup phase of the screening center, she visited the company and was impressed with the ability of its liquid handlers to service a variety of assays. “We were also looking for a strong industry track record and considered our experiences with PerkinElmer’s excellent service.”