Liquid Handling Advances Boost Lab Productivity

Liquid-handling operations, such as pipetting, diluting, and dispensing, are undergoing major changes in today's life science laboratories in response to increased demands for higher productivity and reduced operator interaction. These basic, everyday functions are being improved significantly with a variety of systems that perform more efficiently, use less labor, and often lead to increased accuracy and precision. Single pipettes are expanding to multichannel units, convenient trigger-action devices are more accurately controlling formerly random flow rates, and manual liquid- delivery techniques are being replaced by automated dispensers. Traditional thumb controls are rapidly giving way to computer controls. "There's a trend in the marketplace to improve precision and accuracy by decreasing the amount of operator variability in pipetting," says Paul Chadwick, marketing vice president of Rainin Instrument Co., located in Emeryville, Calif. A manual pipette is totally operated by the user's thumb and therefore subject to variation from one technician to another, he notes. In response to this need for pipetting consistency, Rainin, for example, has developed a microliter pipette, the EDP-Plus, with a motorized, computer-controlled piston drive. A computer regulates the speed at which the motor aspirates the liquid, decreasing the variability of the operation, Chadwick explains. Numerous products are commercially available to accurately transfer liquids. Single and multichannel pipettes, some with digital display, can repetitively dispense fixed aliquots. For example, Labsystems, located in Needham Heights, Mass.; Pittsburgh-based Fisher Scientific; and Coast Scientific in San Diego offer a variety of ergonomically designed liquid- handling devices known as Finnpipettes that deliver a range of volumes. "We use Finnpipettes quite a bit for pipetting biologicals like plasma, urine, and whole blood, and for adding known amounts of standard solutions to our calibration curves," remarks Suemarie Simpson, an assistant scientist in the pharmaceutical division of Oneida Research Services, located in Whitesboro, N.Y. "We couldn't do this type of work, with the precision and accuracy that's required, without them." Simpson points out another important feature of Finnpipettes. They can be calibrated to comply with government regulations and industrial guidelines, such as Good Laboratory Practices. The Pipet-Aid XP from Drummond Scientific Co. of Broomall, Pa., has a pistol-type grip, which allows researchers to exert fingertip control in selecting the most appropriate liquid- filling and discharge speeds for their particular applications. "The light weight and compact size of this portable system make it easy to use under a hood," notes Chuck Locke, Drummond's sales manager. Max, another portable pipettor with push-button operation, is available from New York City-based Manostat Corp. This unit has a built-in memory function for repetitive dispensing. "We use the Max system for general molecular biology reagents and media," reports Alex Chen, a senior research coordinator at Mount Sinai Hospital in New York. "This automated dispensing unit allows us to pick up liquids more accurately, and saves time by mixing them faster." Corning Costar Corp. of Cambridge, Mass., offers the Stripettor, a pipetting aid with trigger-like controls that connects to a vacuum pump for liquid-handling operations. Available with a recharger/adapter option, the unit is designed for use with most pipettes. VENDORS OF LIQUID HANDLING EQUIPMENT AND SUPPLIES Alltech Associates Inc. Deerfield, IL Anpec Co. Ann Arbor, MI Barnstead/Thermolyne Dubuque, IA Beckman Instruments Inc. Fullerton, CA Bellco Glass Vineland, NJ Bio-Rad Laboratories Hercules, CA BioWhittaker Inc. Walkersville, MD Brinkman Instruments Inc. Westbury, NY P.J. Cobert Associates Inc. St. Louis, MO CardCoast Scientific San Diego, CA Cole-Parmer Instrument Co. Niles, IL Continental Laboratory Products San Diego, CA Corning Costar Corp. Cambridge, MA Drummond Scientific Broomall, PA Dynatech Laboratories Inc. Chantilly, VA Fisher Scientific Pittsburgh, PA Gilson Inc. Middleton, WI Hamilton Co. Reno, NV Harvard Apparatus Inc. South Natick, MA Hewlett-Packard Co. San Fernando, CA Isco Inc. Lincoln, NE Labsystems Needham Heights, MA Manostat Corp. New York, NY Marsh Biomedical Products Rochester, NY Matrix Technologies Corp. Lowell, MA Midwest Scientific St. Louis, MO National Scientific Supply Co. San Rafael, CA Oxford Labware St. Louis, MO Packard Instrument Co. Meriden, CT PolyScience Niles, IL Rainin Instrument Co. Inc. Emeryville, CA Research Products Intl. Mt. Prospect, IL Robbins Scientific Corp. Sunnyvale, CA Tecan U.S. Inc. Research Triangle Park, NC Tekmar Co. Cincinnati, OH Thomas Scientific Swedesboro, NJ Tri Continent Scientific Inc. Grass Valley, CA Ulster Scientific New Paltz, NY USA Scientific Plastics Inc. Ocala, FL 34478 Vangard International Neptune, NJ VWR Scientific West Chester, PA Wallac Inc. Gaithersburg, MD Wheaton Scientific Millville, NJ Zymark Corp. Hopkinton, MA The recently introduced Eppendorf EDOS Electronic Dispensing System provides programmable pipetting for volumes ranging from 0.5 microliter to 50 milliters. Available from Brinkmann Instruments Inc., located in Westbury, N.Y., this unit has memory storage for up to 210 customized programs and is designed for high volumes of repetitive dispensing, mixing, and serial dilutions. "EDOS is a motorized liquid-handling system that avoids the risk of repetitive stress injuries, such as carpal tunnel syndrome [a painful or numbing condition of the wrist and hand caused by repetitive movement], which often results from high- volume manual pipetting," claims John Woods, Brinkmann's director of marketing. A further benefit, Woods maintains, is that once the system is programmed to dispense a set amount, the motorized design ensures that amount will be delivered every time: "Manual pipetting is subject to error because everybody pipettes a little bit differently." The Microlab Diluter/Dispenser, available from Reno, Nev.- based Hamilton Co., also replaces manual pipetting. These motorized devices control the amount of fluid dispensed from either one or two syringes, according to Robert Lund, Hamilton's marketing director. Through the touch of a hand probe button, the Microlab diluter aspirates a sample and then dispenses it into a container along with a desired volume of diluent, he notes. Liquid-delivery devices that provide for the continuous infusion or withdrawal of volumes over extended periods are known as syringe pumps. Fully programmable systems offering various control benefits, including changes in flow rate, are now available from Harvard Apparatus of South Natick, Mass. "We use Harvard syringe pumps for the microinfusion of various drugs into the brain in [connection with] our research studies on epilepsy," says Pravin Mishra, an assistant professor of pharmacology at the University of Illinois College of Medicine in Peoria. "We infuse liquids at a very slow flow rate, and the microprocessor-controlled pump maintains the desired infusion rate very accurately." Some liquid-handling systems mount directly onto reagent bottles, providing a ready reservoir of frequently used solutions. For example, the REPIPET dispensers from Barnstead/Thermolyne of Dubuque, Iowa, are available in a variety of sizes and configurations. Also available are the Single-Stroke Dilutors, which reportedly require only about six seconds to complete a full cycle of aspiration and dilution. Another bottle-mounted system is the new Liquid Processor Burette, from PolyScience in Niles, Ill. Microprocessor- controlled, the unit provides dispensing of set volumes, as well as time-controlled dispensing from one second to 100 hours, over a range of 10 ml to 100 ml. It also has a dilution feature. An RS232 interface permits PC programming control of all functions, and relevent information is indicated on a two- line LCD display. "This combination pipette, buret, and dilutor allows for very precise dispensing because it has no valves and [essentially] no stored volume of liquid that can create inaccuracies due to changes in vapor pressure," explains Philip Preston, president of PolyScience. The system is as chemically inert as Teflon, and can operate with most acids, bases, and organic solvents, he claims. "The trend in drug discovery is to go faster, and researchers are always looking for new ways to improve their productivity," comments Andre Proulx, an applications specialist at Hopkinton, Mass.-based Zymark Corp. The reason behind this desire for increased speed is that screening for novel drug leads has become a numbers game. Large numbers of compounds are screened against enzymes, receptors, and other biologically relevent targets, requiring hundreds of thousands of assays to obtain the bioactive "hits" needed to feed a productive drug-development pipeline. Researchers not only want to do their assays as quickly as possible without compromising precision, but also want to keep the solution volumes low because the samples are very precious and the reagents are very expensive, explains Proulx. Typical volumes range from 10 to 200 microliters. Using a Zymark AutoPlate-96 Workstation in conjunction with robotics, Randy Schatzman, the cell biology department head at Syntex Discovery Research Corp., located in Palo Alto, Calif., conducts high-throughput screening for his drug-discovery projects. "The Zymark system allows us to fully automate biochemical-type assays, where we want to rapidly screen hundreds of thousands of compounds to see if we can randomly identify inhibitors and use those as lead structures for chemical follow-up," he says. The system pipettes the assays, setting them up in 96-well plates, and performs the desired assays unattended for up to 24 hours. The laboratory technicians are thoroughly trained in the use of the equipment, and can trouble-shoot problems as well as do minor repairs. "When we're doing a hundred thousand compounds a year, a few days of downtime is very significant to our throughput," Schatzman points out. Initially, lab workers did a lot of the liquid-handling steps by hand, but then began to automate these procedures by moving to liquid-handling platforms that could perform multiple pipetting operations at one time. However, as scientists change their methodology, they generally conduct validation studies, comparing results obtained manually with those acquired from the automated systems. "Recently, we conducted an in-depth study comparing the precision and accuracy of automated sample preparation to manual preparation using Class A volumetric glassware--the industry standard for performing aqueous dilutions by hand," says Todd Wielgos, a senior research associate in corporate research and technical services at Deerfield, Ill.-based Baxter International Inc., a provider of health-care equipment and supplies. "Preparing samples for high-performance liquid chromatographic [HPLC] analysis is a tedious, time-consuming task, [so] we are constantly seeking ways to increase productivity while maintaining the high quality of our results," explains Wielgos. The Baxter chemists often perform routine dilutions, "and, when conducting stability testing, it is not unusual for an analyst to spend the entire day making dilutions for overnight HPLC runs. "By automating, we hope both to increase sample throughput and to free up our lab people to perform more challenging and valuable analytical work." An HP 7686 PrepStation from Hewlett-Packard Co., located in Palo Alto, Calif., was selected to handle the automated sample preparation. Samples and standards prepared by both methods were injected into an HPLC system on the same day in serial runs. Baxter's Applied Statistics Center evaluated the results and concluded that the HP PrepStation and Class A volumetric glassware yielded statistically identical results over the range of dilution factors from 2 to 200. The automated approach offers significant advantages over manual sample preparation, such as achieving accurate and reliable results 24 hours a day, reducing human exposure to toxins within the laboratory, and allowing the analyst to "spend more time doing creative, meaningful work," according to Wielgos. Enhanced Applications Laboratory assays and techniques should generally improve as researchers become more familiar with automated liquid- handling equipment. "We look at the benefits of commercially available automated systems, and focus on developing applications for them," says Robin Felder, an associate professor of pathology at the University of Virginia and the director of the university's Center for Research on Medical Automation. Often, equipment manufacturers don't realize their device is useful for a certain application, so Felder points it out to them. For example, he says, "We have developed a glycated hemoglobin procedure on a Hamilton Microlab 2200, and a reverse transcriptase PCR [polymerase chain reaction] assay on a Packard MultiPROBE," from Packard Instrument Co., Meriden, Conn. In addition, Felder's group addresses such issues as standardization, connectivity, and safety. Felder is currently using Middleton, Wis.-based Gil-son Inc.'s 215 Automated Liquid Handling System to process blood samples for several screening tests. "The advantage of this system is [its ability] to pierce the rubber caps of primary tubes, thus providing a totally closed system, and avoid handling the customary open tubes that may contain potentially toxic viruses. That's an important safety feature," he stresses. Also benefiting from the Gilson 215's cap-piercing feature is Primus Corp., a Kansas City, Mo.-based medical diagnostics company. "We have converted the system to be specifically dedicated as the front end of our glycated hemoglobin analyzer," says Rick Harrison, Primus' vice president of operations. "It's an outstanding application for us because it saves a great deal of repetitive-motion labor for our clients, and has eliminated the ergonomic problems of having to crimp a cap onto each one of the sample vials. The system also provides an important safety feature for users, since they no longer have to open those tubes and produce blood aerosols." Neil Gershman, manager of virology and serology at Sonora Laboratory Sciences in Phoenix, agrees that automated liquid handling reduces the risk of exposure to toxic materials. "We're using a BioWhittaker [Inc. of Walkersville, Md.] Wellprep 2000 for serologic testing of serum samples, and this system avoids having a technologist do hand-pipetting of patient specimens," he says. "There's always some safety concerns when dealing with patients." In addition, according to Gershman, quality control is much easier to track when there is only one instrument performing all the different parameters of the test: "If the assay were done manually over different areas of a bench, there may be several pieces of equipment that would need quality control monitoring." The Biomek 2000 from Fullerton, Calif.-based Beckman Instruments is another automated workstation that performs liquid-handling procedures. "The primary applications have been for microtiter plate-based assays that require extensive pipetting, diluting, and dispensing," says Charles Powell, Beckman's North American product-marketing manager for robotics. Interchangeable liquid-handling tools allow the researcher to set up the system according to assay requirements and automatically select accurate transfer volumes from 1 to 150 microliters. "Without a doubt, the Biomek allows me to be more productive," asserts Jim Chambers, the director of the DNAcore and the sequencing discovery group at R.W. Johnson Pharmaceutical Research Institute, located in La Jolla, Calif. Performing large numbers of sequencing reactions, Chambers, using a modified tool, pumps a slurry right through the automated machine into a 96-column format for the final purification step. "Now we're able to spin 384 columns at once, and still be productive doing something " he notes. Robbins Scientific Corp., located in Sunnyvale, Calif., recently introduced the Hydra-96 Microdispenser, a system that provides microliter dispensing through 96 channels with glass syringes that fill and dispense in unison. The instrument delivers volumes as low as 0.5 ml per channel. "We use the Hydra-96 to dispense all the reagents that are used for PCR amplification into 96-well trays," says Jan Capper, the laboratory director in the department of immunogenetics and transplantation at the University of California, San Francisco. "We pre-plate our trays with all the PCR ingredients and freeze them for future use, and this system enables us to pre-dispense without having to do it by hand." GENESIS SERIES represents another fully automated liquid- handling system designed for high-throughput microplate processing. Available from Tecan U.S. Inc., based in Research Triangle Park, N.C., the modular concept allows complete flexibility in containers, tips, and carrier positioning. Positive identification is also achieved, as bar codes can be read by the system horizontally or vertically on any container on the work surface. Wallac Inc., located in Gaithersburg, Md., offers the Quadra 96, the company's version of a 96-well pipetting system. Operating in unison, the pipettes deliver up to 450 microliters of solution under the user's set program protocol. "We use the instrument primarily to make mother/daughter plates for drug screening," says John Nygaard, manager of robotics and screening at Microside Pharmaceuticals Inc. of Mountain View, Calif. "We use a 96-well plate and deliver aliquots above 100 microliters. I view the program on my PC and can up- and download the program into the machine, which really facilitates programming." Beckman's Powell points out that the trends he sees in liquid handling are driven primarily by speed: "If we could move to higher densities, for example, to a 384-well plate from a 96- well plate, we can process more samples in a shorter amount of time and obtain more information faster." However, he says, this would require a redesign of detection systems, as well as extensive revisions to the spatial resolution of the plate, and "that technology is just now coming to the forefront."

Liquid Handling Advances Boost Lab Productivity

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