Automated Liquid Handlers Advance

Automated liquid handling continues to play a central role in laboratory automation. These robots rapidly, tirelessly, and accurately perform a range of tedious liquid-handling tasks, such as assay setup, plate filling, plate washing, and hit picking. They carry out these functions on liquid vessels that range from standard test tubes to 1536-well plates, and they benefit researchers in such diverse fields as drug discovery, genomics, proteomics, and clinical research.1 Automated liquid handling technology has changed considerably since The Scientist last examined it in 1999.2 Manufacturers have improved and modified existing automated liquid handlers to adapt to the customers' rapidly evolving needs, incorporating cutting-edge technology, and applying the practical experience gained over the past few years. Courtesy of Hamilton Co.Diligent & Tireless: Liquid-handling robots automate the day-to-day tedium of lab work, performing such tasks as plate filling and washing and assay setup, as well as DNA preparation and hit picking. Shown here is Hamilton's MICROLAB STAR. The MICROLAB STAR, recently introduced by Reno, Nev.-based Hamilton Co., is a good example of the improvements. "The MICROLAB STAR project started as a program to solve deficiencies we saw with air displacement pipettes and the needs of the drug discovery and drug development industries," explains product manager Dave Hansen. The resulting instrument boasts advanced pipetting and probe-positioning capabilities among other innovative features. However, not everyone who needs automated pipetting capabilities requires, or can afford, a $75,000 system. Consequently, companies developed instruments to fill the gap between hand-held electronic pipettors and the larger, expensive pipetting robots. Nichiryo America Inc. of Flanders, NJ, is committed to filling this gap. "There is a definite market for this type of equipment. We receive numerous inquiries from universities and researchers looking to use liquid handlers in a casual manner," explains company president Sada Tanabe. These devices strike a chord with users that have "medium-throughput" microplate workloads. According to Jason Green, product manager, Bio-Tek Instruments of Winooski, Vt., the company's Precision 2000 Automated Microplate Pipetting System was designed to accommodate such customers. "Our goal was to develop an instrument that can do anything a user does with a manual pipette, but in an automated fashion. We also wanted to keep our design very cost-effective," he says. Nicole Lisi, product manager for Beverly, Mass.-based Thermo Orion, comments that the small size of these economical liquid handlers appeals to researchers. "Many of our customers have approached us with applications that require placing the liquid handler into a sterile environment. Unlike the larger liquid handlers, the small size of our instruments facilitates their use in laminar flow hoods," she says. Overall, the industry is moving toward higher-throughput devices and improved modularity. The use of high-density 384- and 1536-well plates has forced the refinement of small volume pipetting capabilities, multichannel pipetting, and dispensing. At the same time, enhanced modularity means that users can assemble systems with only the features they require, thereby reducing cost. There is also a trend toward smaller, application-specific systems--for example, systems designed to carry out DNA mini preps. In short, there are more automated liquid-handling options available, which researchers can more precisely model to their specific needs. What follows is a summary of available automated liquid handlers: Applied Biosystems: A four-tip, liquid-level-sensing robotic arm supplies liquid handling capabilities to Foster City, Calif.-based Applied Biosystems' ABI PRISM 6700 Automated Nucleic Acid Workstation. The 6700 purifies total RNA and DNA from complex biological samples, produces cDNA, and prepares PCR reactions. Another instrument, the COBRA™ Robotic Sample Handling System, provides fraction collection and sample re-injection capabilities to Applied Biosystems' BioCAD 700E liquid chromatography workstations. The COBRA system also functions as an independent sampler or collector. Beckman Coulter Inc.: The Fullerton, Calif.-based company has expanded its liquid handlers' flexibility with the introduction of the Biomek® FX Liquid Handling System. In its single pipetting arm configuration, the Biomek FX runs either the Span-8 Pipettor, with eight independent channels, or a 96- or 384-channel pipetting head. The dual-arm version enables simultaneous pipetting functions by combining any feature of the Span-8, 96-, or 384-channel pipetting head in a single platform, allowing liquid transfers across any format, from tubes all the way up to 1536-well plates. The Biomek FX's standard, modular design allows the use of fully interchangeable components in the form of Automated Labware Positions (ALPs). ALPs perform application-specific tasks such as plate shaking or vacuum filtration, simplifying the system's configuration for specific applications. In addition, Beckman Coulter has recently upgraded its time-tested Multimek™ 96/384-Channel Automated Pipettor with a new 384-channel pipetting head. Incorporating air-displacement pipetting technology and proprietary pipette tips, the new head delivers precise liquid transfers in the 1-30 ml range. Bio-Tek Instruments: Priced under $16,000, Bio-Tek's Precision 2000 and Precision 2000 Plus 96/384-Well Automated Microplate Pipetting Systems handle several routine liquid-transfer operations. Both models come equipped with a user-configurable, six-station platform that accommodates reagent troughs, disposable tips, and up to six 96- or 384-well microplates. An eight-channel pipettor is standard on both instruments; the Precision 2000 Plus also features an eight-channel continuous reagent-dispense manifold. Up to 80 programs on the on-board microprocessor drive the Precision 2000, but operation through an external PC is available. Bio-Tek also offers the mFill Reagent Dispenser, which rapidly dispenses a continuous reagent into 96-, 384-, and deep-well plates. The mFill has a small footprint and is designed to be robot compatible. Cartesian Technologies Inc.: Irvine, Calif.-based Cartesian Technologies' synQUAD™ technology is capable of quantitatively dispensing volumes as small as 20 nanoliters (nl). This proprietary technology couples an XYZ motion-control system with the high-precision capabilities of a syringe pump and the high-speed actuation of a micro-solenoid valve. When carefully synchronized, these components function together as a precise, non-contact nanoliter delivery system. The system confers numerous advantages to the plate-filling process, according to Don Rose, vice president, R&D. "The fluidic inertia from the ejected reagent creates mixing with the wells. This is an important benefit when filling 1536-well plates because mixing is otherwise performed by some mechanical means like pipetting the well contents up-and-down," he says. Cartesian's SQ Series of dispensing workstations, based on synQUAD technology, handle high-speed plate filling of 384- and 1536-well plates across a dynamic dispensing range of 0.02-250 ml. Up to eight channels independently dispense eight different reagents, including bead suspensions. Cartesian also offers the HummingBird™ technology for parallel transfer of nanoliter sample volumes. Developed by GlaxoSmithKline of Stevanage, U.K., HummingBird uses 96 or 384 glass capillaries to "sip" the samples (25-500 nl) from a source plate and then "blow" them out into microwell plates using air pressure. The technology involves no moving parts, has no sample wasted due to dilution, and provides non-contact sample transfer. Cavro Scientific Instruments Inc.: San Jose, Calif.-based Cavro supplies OEM products for automated liquid handling. A Tecan Group company, Cavro's Mini Sample Processors automate lab activities utilizing cap-piercing probes, disposable-tip probes, and eight-tip probe manifolds as liquid-handling tools. The company's robotic technology embraces bare XYZ positioning modules or completely packaged stand-alone systems. Cavro also offers a wide selection of OEM syringe pumps and liquid-handling modules. Colibri Robotics: New Castle, Del.-based Colibri Robotics offers two modular systems for robotic microplate processing: the Plato 3 Series processor, featuring a number of optional modules, and the Xantus, whose design focuses robotic and liquid handling functionality in the robotic arm. The arm glides on a multi-length X-bar to access both the workspace and integrated or surrounding modules. Available in single- and dual-arm versions, the Xantus can be equipped with up to 16 sampling tips, or up to 12 tips and a 360º rotating robotic handler. CRS Robotics Corp.: Based around its proprietary Polara™ software, Burlington, Ontario, Canada-based CRS Robotics combines liquid handlers and other components into automated systems that accelerate testing and analysis of critical elements for product-development pathways. The CRS DNA Amplification System, for example, combines a Packard MultiPROBE II with MJ Research's Tetrad thermocycler and other components into a system capable of performing a complete DNA amplification protocol; this system accommodates up to 120 microplates. CRS offers additional systems, such as the CRS DNA Purification System and automated cell-based assay systems, as well as custom-designed systems and OEM services. Gilson Inc.: Middleton, Wis.-based Gilson's recent acquisition of Cyberlab Inc. brings years of liquid handling and chromatography experience to the company, resulting in the development of a number of automated liquid handling systems. Gilson's latest innovation, the Constellation™ 1200 Liquid Handler, is an XYZ robot designed to deliver accurate and precise nanoliter volumes for high-throughput applications. The Nebula™ 215 series covers several sample-preparation applications, including solid-phase extraction with the SPE 215 system. In addition, the 215 Liquid Handler provides sample injection and fraction collection for both HPLC and Gilson's Nebula LC/MS Purification System. Cyberlab's automated plate-preparation workstations have a work deck capacity of over 400 microplates and feature a multifunctional XY carriage that holds up to six pipetting tools and a plate gripper. Hamilton Co.: Monitored air-displacement technology on board Hamilton's MICROLAB STAR's eight liquid probes enables each to detect insufficient reagent levels or clogged tips. A combination of capacitance and pressure-based liquid-level detection mechanisms allows the STAR to detect liquid levels under bubbles and to find the interface between immiscible aqueous and organic phases. This unique ability permits the automation of liquid/liquid extractions. In addition, all eight probes move independently along the Y-axis. They can be spread unevenly across the work surface, facilitating hit picking or tube-to-microplate transfer applications. J-KEM Scientific Inc.: Developed for weighing, process chemistry optimization, solid- and solution-phase synthesis, and solid-phase extraction methodologies, St. Louis-based J-KEM Scientific's Phoenix Robotic Workstations are easily reconfigured to meet a researcher's changing needs. For example, a workstation configured for solid phase extraction can be readily changed into a workstation equipped for weighing and reaction mapping procedures. The Phoenix systems rely on J-KEM's Robotic Controller, which converts English-style string commands into workstation actions. Matrix Technologies Corp.: Designed for high-throughput screening applications with the incorporation of four universal plate-stacker chimneys, Hudson, NH-based Matrix Technologies' PlateMate Plus workstation drives a choice of five separate 96- or 384-channel pipetting heads to process not only 96- and 384-well plates, but 864- and 1536-well plates as well. Accessories include peristaltic pumps, tip wash stations, and serial dilution mechanics. Matrix has also upgraded its SerialMate Microplate Pipetting System to include a 16-channel version designed for 384-well plates. An alternative to tedious manual pipetting, the SerialMate pipettors offer cost-effective automation of procedures like serial dilution, reagent addition, and plate replication. Mettler-TOLEDO Bohdan Inc.: Mettler-Toledo Bohdan of Vernon Hills, Ill., offers several automated instruments developed to assist chemists involved in drug discovery and development. The recently introduced Universal Sample Preparation (USP) incorporates liquid handling into its automated weighing, reagent preparation, and compound work-up functionalities. Its modular hardware also offers vortexing, sonicating, and tube capping and uncapping capabilities. Bohden's ALLEX™ automates sample work-up via separatory funnel techniques, with functions including solvent and wash solution addition, sample mixing, phase separation, and phase distribution via proprietary phase boundary-sensing technology. Finally, the PDW200 automates the scale-up procedures required to produce larger amounts of new drug candidates identified by high throughput screening technology. Molecular Devices: Sunnyvale, Calif.-based Molecular Devices' AQUAmax™ 1536 Dispenser is a non-contact, fixed-tip dispenser capable of filling 1536 wells in 30 seconds. Handling a volume range of 0.5-10.0 ml, the AQUAmax also dispenses bead suspensions for scintillation-proximity assays as well as suspensions of cells up to 15 mm in diameter. Nichiryo America Inc.: Nichiryo offers eight compact and inexpensively priced liquid-handling workstations. The CHOT-1 and CHOT-2 are single-probe microplate preparation tools with three-position work decks for 6-to-384-well plates or deep-well plates. The CHOT-8 and CHOT-12 use 8- or 12-channel pipettors with disposable tips, respectively. Nichiryo also focuses on pre-designed instruments for specific applications. The company developed the CHOT-4, for instance, to run Caco-2 assays, whereas the CHOT-5 handles solid-phase extraction procedures. Perkinelmer Life Sciences: Boston-based PerkinElmer Life Sciences offers application-ready solutions through its Packard brand automated liquid-handling systems, including the four-channel MultiPROBE II and the newer eight-channel MultiPROBE II HT. Besides liquid-level detection capabilities, enhanced positioning reproducibility for 384-well plates, and sub-microliter pipetting abilities, the MultiPROBE instruments include expanded versions, including an optional gantry-based gripper system. For higher throughput and increased capacity, PerkinElmer's Packard PlateTrak product line offers high-speed robots with 96- and 384-channel dispensing, microplate stackers, and a bi-directional conveyor for high-speed parallel processing. Specialized PlateTrak models include the smaller, standardized MiniTrak system; the ImageTrak system for integrated liquid handling and cell-based fluorescent imaging; and the DNATrak for high-speed nucleic acid and PCR purification, dye terminator removal, and sequencing reaction assembly. QIAGEN Inc.: Valencia, Calif.-based QIAGEN's BioRobot® 3000 features four worktable sizes with numerous layout options, allowing users to prepare any configuration required, or to choose only those modules and accessories they desire. QIAGEN also offers left- and-right handed extended arm configurations to integrate external instruments like plate readers, thermal cyclers, or QIAGEN's new BioRobot RapidPlate 96- and 384-well dispensers. Robbins Scientific Corp.: Sunnyvale, Calif.-based Robbins Scientific's Hydra Microdispensers employ an array of 96 or 384 high-quality glass syringes arranged in a grid corresponding to the exact centers of a microplate's wells. A precision motor assembly drives the syringe plungers. Coupled with the exact movements of a motorized sample platform, the Hydras accurately dispense liquids into the bottom of dry plates or onto various transfer membranes. Reagents from various source plates can also be collected sequentially into the syringes and then dispensed together into one assay plate. The Hydra Microdispensers can be upgraded with increasing levels of automation to include an automated wash system, two-position XY stage, and plate stacker. Robbins has expanded the Hydra's capabilities with the development of the new Tango Liquid Handling System. Designed for high-throughput screening, genomics, and proteomics applications, the Tango system combines the Hydra's low-volume capabilities with a 12-position stage. It features a choice of eight dispensing heads for pipetting liquids, beads, or resins into 96-, 384-, and 1536-well plates. Tecan U.S.: Research Triangle Park, NC-based Tecan offers several liquid-handling systems. The compact and economical MiniPrep 60 and MiniPrep 75 Mini Sample Processors support a variety of drug discovery, molecular biology, and diagnostic applications. For example, the MiniPrep 60 MolBio Workstation uses a vacuum solid-phase extraction system to automate DNA-preparation tasks. Many predefined kits are now available as well, as are customized procedures. Tecan's Genesis Series of Robotic Sample Processors (RSPs) combine an adaptable workstation, advanced pipetting, liquid detection, sample identification, and integration capabilities into three versatile liquid-handling systems. A robotic manipulator arm extends the level of automation by transporting plates to other instrumentation, such as plate readers or washers, and enables the manipulation of plates and reservoirs on the work surface. The new Genesis Freedom Series allows for multiple robotic manipulator arms, including extended-reach arms that can access additional modules beneath the worktable. Applications currently automated by the Genesis RSPs include plasmid DNA preparation, DNA quantification, and cell permeability assays. Tecan's MiniLyser and MiniSwift systems incorporate plate readers, washers, and incubators to process up to 180,000 ELISAs per year. Thermo Labsystems: Franklin, Mass.-based Thermo Labsystems has applied the philosophy behind its successful Multidrop plate dispensers to the development of one of its newest products, the Wellpro 384. The Wellpro 384 employs a 16- or 24-channel dispensing head to easily tackle jobs like dilutions, plate replicating, and dispensing in 384-well plates. Thermo Orion: Beverly, Mass.-based Thermo Orion recently introduced an affordable line of robotic liquid-handling automation systems comprised of the AS2000, AS2500, and the AS4000 models. Designed to do everything the larger systems do but on a smaller scale, these systems can be configured with up to eight fixed-needle probes or a single-channel, disposable pipette system. The AS4000 also features an eight-channel disposable tip pipettor. Titertek Instruments Inc.: Combining Thermo Labsystems' Multidrop 384 with proven microplate stacking technology, Huntsville, Ala.-based Titertek Instruments offers an automated plate-filling instrument that handles up to 60 plates without intervention. The Multidrop 384 Stacker processes 96- and 384-well plates, and dispenses 5-395 ml per well. Tomtec Inc.: The Quadra product line from Hamden, Conn.-based TOMTEC offers a unique concept in liquid handling. These instruments employ a six- or eight-station shuttle that moves plates and reagent reservoirs to and from the pipetting head. Coupled with an indexing stage, source and destination plates are easily accessed for plate reformatting. Additionally, the Quadra's moving multi-station platform and air-gap-separation-of-reagents concept allows for the addition of multiple reagents to a single plate in one pass. Three pipetting head configurations are available for 96- and 384-well plates, including positive-displacement small-volume heads that deliver 500 nl with CV's of 2-3%. Plate stackers increase throughput up to 100 plates. Zymark Corp.: In addition to its proven RapidPlate® 96/384 Microplate Pipetting Workstation, Hopkinton, Mass.-based Zymark offers the Sciclone Advanced Liquid Handler (ALH). This system features several dispensing options, including three multi-channel head types. The high volume (HV) head accommodates 96 disposable tip attachments and is capable of indexing into 384 wells; the low volume (LV) head accommodates 96, 384, and 384/1536 fixed cannulae; and a third head has the capability of 384 dispensing of 100 ml and will be released in the beginning of 2002. The ALH also features an independent Z8 head option, which enables the researcher to use eight individual aspiration and dispensing cannulae. These include fixed tips, disposable tips, or a combination of each, as well as a bulk reagent dispenser, which allows bulk fluids to be dispensed in an eight-pin cannula driven by syringes, peristaltic pump, or a combination of both. Michael Brush (michaeldbrush@cs.com) is a freelance writer in Tustin, Calif. References 1. J. Boguslavsky, "Industrializing structural proteomics," Genomics and Proteomics, 1[2]:46, September/October 2001. 2. M. Brush, "Automated laboratories," The Scientist, 13[4]:22, Feb. 15, 1999. Supplemental Materials Automated Liquid Handlers

Automated Liquid Handlers Advance

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