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The Lab Manager AUTOMATED LIQUID HANDLING RESOURCE GUIDE

What You Need to Know When Buying an Automated Liquid Handling System BY RYAN ACKERMAN

Upgrading Stand-Alone Automated Liquid Handling Systems to Workstations BY ANGELO DEPALMA, PhD

Small-Volume Liquid Handling Requires Advanced Technology BY MIKE MAY, PhD 20 10 Common Liquid Handling Errors & How to Avoid Them 17 BY LAB MANAGER

The Latest in Pipette Tip Design BY ANGELO DEPALMA, PhD

Automated Liquid Handling Product Finder BY LAB MANAGER Automatic Liquid Handling Resource Guide 2017

What You Need to Know When Buying an Automated Liquid Handling System Automated liquid handlers come in a seemingly endless variety of configurations, with many different specifications.

By Ryan Ackerman

MAINTENANCE TIP: AUTOMATED LIQUID HANDLING The signs that you should get your automated liquid handler serviced are fairly obvious. If the system is constantly experiencing glitches or producing inconsistent, unreliable results, it’s probably time to do some maintenance. Mechanical problems are another hint that you may want to call your service technician—these issues can include pipette tips being out of calibration, the deck not being “framed” correctly, belts being worn out, or the pipette stages being out of alignment.

Why is it important to know the typical sample How does the sensitivity to contamination affect the type volume being used? of automated liquid handler required?

Automated liquid handlers come in a seemingly endless variety of As the instrumentation used to analyze samples becomes more configurations, with many different specifications. An important one sensitive, the methods used to transport and prepare the samples to consider is what minimum, or maximum dispensing volume is must become resistant to contamination to ensure no carryover correct for your processes. If your sample volume is highly variable, occurs. In order to combat contamination, vendors have updated getting a more robust station capable of low-range and high-range systems to use a variety of different materials for sample probes volume dispensing is worth considering. and sample flow areas, along with more proficient rinsing abilities. For low volume samples there are a variety of non-contact options Will process type and downstream analysis affect the which utilize a variety of different methods. type or set-up of automated liquid handler required?

With ever-increasing needs for high sample throughput and automation in , the available options for integrated automated liquid handling systems have increased dramatically. Whether you are looking to automate DNA/RNA preparation, PCR, ELISA tests, next generation sequencing, solid phase extractions, liquid-liquid extractions, or combination systems capable of barcode tracking as well, the possibilities are many in the liquid handling domain.

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Upgrading Stand-Alone Automated Liquid Handling Systems to Workstations Automated liquid handlers have become indispensable by virtue of freeing operators for other tasks while providing consistency and reproducibility.

By Angelo DePalma, PhD

or downstream of the liquid handler. Joby Jenkins, global head of liquid handling at TTP Labtech (Melbourn, UK), notes that timing is everything. “Having someone move plates onto and away from the liquid handler is fine if that process is isolated and the worker can go off for an hour or two in between.” But workstations make sense if the dispensing step is rapid and followed by another relatively short step, requiring the worker to keep an eye on operations.

Labs in upgrade mode have probably identified process inefficiencies for liquid handlers they already own. Labs in total acquisition mode, for example, those that take on new projects, have the luxury of choosing a ready-built workstation. Many labs today employ automated liquid handlers as stand-alone devices, moving plates manually onto and off the stage to storage, Jenkins advises the latter not to over-specify workstations to incubators, and readers. Integrating liquid handlers with other features accommodate every conceivable anticipated future need. “Defining or functions—that is, turning them into workstations—is attractive, both current and future processes is difficult. If you specify a system but the path to fuller automation can be costly and lengthy. that does everything, it will be large, expensive, and complex. You can simplify the process massively by choosing systems that have the Paul Held, PhD, manager at BioTek Instruments flexibility to grow with changing business needs. Reducing the initial (Winooski, VT) defines a liquid handling workstation as a investment is attractive to many start-up or smallto- middle-sized multicomponent system, as opposed to “an automated pipettor and businesses.” a computer.” Workstations tend to be modular, consisting of two or more functions (dispensing, aspiration, storage, incubation, shaking, Upgrading, moreover, has simplified compared with even five reading, lidding/unlidding, etc.) and operated in semiautomated or years ago. Software is more flexible, and vendors are designing fully automated fashion. their components specifically for integration and automation. Labs would be better off, Jenkins notes, if instead of over-specifying for Workstations also can be defined based on purpose rather than functionality, they focused on flexibility. This allows for purchasing instrumentation and connectivity, for example, as a setup dedicated exactly what is needed today, with a smooth path toward upgrading to PCR or the same panel of biochemical assays day in and day later. out. But the difference between that definition and the one based on integration, Held says, is “pure semantics.” “The best approach when adding functionality is to deliver a solution that meets your immediate needs but doesn’t limit any future features “The appeal of workstations is that you get an efficient, easy-to-use you may require,” comments Jackson. platform tailored to your methods. The risk of workstations is that usually the simplicity comes at the cost of flexibility,” adds Del Plusses and minuses Jackson, product manager at Hamilton Company (Reno, NV). Both upgrade and “one and done” approaches have advantages and Upgrade considerations disadvantages.

Upgrading from a stand-alone dispensing system to a workstation “If you buy everything at the same time, it’s one big purchase order involves adding one or more functionalities occurring upstream and you’re done with it,” Paul Held observes. Labs are assured

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the pieces will work together, and may enjoy a more harmonious needs. “Workstations differ from devices that execute only one action customer support experience later on. Piecing systems together of a workflow,” he says. “Consider all the steps in your daily routines. requires automation savvy, but affords less experienced labs the luxury For example, is there a DNA extraction before PCR? Do samples of learning how each piece works before investing in the next step. need preparation for ? There are a number of ways to do any of this. Workstations should provide method flexibility.” “Experienced labs with a good grasp of what it takes to automate an assay will generally purchase everything they need to accomplish Before upgrading stand-alone liquid handlers to workstation status, lab that task,” Held adds. They also tend to anticipate better how their managers should identify frequently occurring, repetitive workflow fluid handling tasks will change over time, and purchase integrated operations that might be causing bottlenecks. Failing to take stock in systems—or components—accordingly. this manner often leads to failure, according to Wehrenberg. “Before speaking with a vendor, managers must ask themselves which tasks are Newcomers often fail in their automation goals because they perceive growing, complex, and justify automation. Where would automation the problem to be less intricate than it actually is. “The nuances of allow scientists to work on something else while a workstation takes on automation can overwhelm them,” Held says. what they are doing today?”

Labs should always become acquainted with an assay’s manual Automation is not all about throughput and walkaway time. operation before considering automation. Only after breaking an Reproducibility and uniformity are necessary for tasks where assay down to its component parts can a manager decide the level pipetting accuracy is critical. If five people work on the same pipetting and extent of automation required to improve productivity. The task, a robot and automated liquid handler will always be more worst strategy is attempting to automate every operation through one reproducible and consistent. purchase. Regardless of the acquisition path, deploying lab automation Held advises lab managers to “understand their process before intelligently and cost-effectively is difficult for resource-constrained even thinking of automation. Pipette things manually, move plates laboratories. Managers may fret over potential missteps with their first manually, and then incrementally add [automated] liquid handling, and subsequent automation components. Wehrenberg advises these then plate movement. A lab doing an assay with an eight-channel customers to err on the side of flexibility and upgradability rather pipette into a few dozen plates per day learns a tremendous amount than cost. about its needs before adding a dispensing device. Labs will have different end points in terms of how automation benefits them.” Once a workstation is installed, lab managers frequently identify further optimization points to accommodate new assays, which will Flexibility is the key require integrating additional devices or adding modules to the liquid handler. “You might find what appears to be an inexpensive solution Hal Wehrenberg, software product manager at Tecan (Männedorf, today only to discover it’s a one-trick pony, and now you need a whole Switzerland) defines a workstation as an integrated instrument system new system to accommodate a relatively minor change,” Wehrenberg built around specific workflows, but flexible enough to meet future says.

Automated Liquid Handling Product Finder Liquid handlers are gaining in popularity in all types of laboratories because they offer significant man-hour savings through automation. However, the range of automated liquid handlers available may be overwhelming, making it difficult to decide what would be the best choice for the unique circumstances of your laboratory.

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Small-Volume Liquid Handling Requires Advanced Technology The evolution of liquid handling involves various parameters, and one of them is volume.

By Mike May, PhD

proteomics research can focus primarily in the microliter range.” Other areas use even smaller samples.

According to Edwards, “Drug discovery and compound screening can be in the pico- to nanoliter ranges and require special types of liquid handlers, such as acoustic dispensers for ultra-low-volume dispenses.” He adds, “A recent trend we have also seen is the need to dispense very small volumes that contain only single cells for genomics analysis.”

Transfer tech tips

“Classic liquid handling—aspiration and dispense—can work down to volumes of a few hundred nanoliters, but that requires heavy optimization,” Overkamp explains. “The key to success is a How low you go depends on the application combination of ultra-precise pipetting heads, high-quality pipette tips, and software that allows the control of the pipetting action in Scientists often try to protect hard-to-get samples by working with ultimate detail and precision.” smaller amounts of them. What is considered “small,” though, varies. As Stefan Overkamp, field marketing manager, automation and As scientists need to work with even smaller volumes, that requires genomics, at Beckman Coulter (Indianapolis, IN) says, what is small more advanced technology. “If you go below this volume range, say “kind of depends on the actual application you are looking at.” He to the single- or two-digit nanoliter area, or even down to picoliters, adds, “A low volume in DNA extraction from blood is not necessarily other technologies need to be applied,” Overkamp says. “These can considered a low volume in ultrahigh throughput screening, but in be simple pin tools, acoustic impulse techniques, piezo technologies, general, ‘low volume’ in liquid handling refers to volumes below 1 or pressure systems with precise valves.” He adds, “None of these microliter.” technologies allow for classic liquid

At the University of Texas at Austin’s Institute for Cellular and Beckman Coulter focuses on classic liquid handling. With the Molecular , for example, Arthur F. Monzingo, manager company’s hardware, pipette tips, and control software, says of the macromolecular crystallography facility, uses the Crystal Overkamp, “customers have been able to get good pipetting results Phoenix from Art Robbins Instruments (Sunnyvale, CA) in preparing down to several hundred nanoliters.” Plus, he adds, “If lower volumes experiments. The smallest volumes that he uses are are required in an assay, we can offer complete automated solutions 0.1 microliters. When asked about the key challenges in using liquid by integrating dedicated low-volume devices into our Biomek handling to transfer such small volumes, he says that they are the workstations.” “accuracy of the volume, accuracy of the location of the transfer, and speed.” Fine-tuning transfers

For an overview of dispensing sizes, David J. Edwards, senior director, The characteristics of the liquid must also be considered, because “the mass spectrometrymarketing, life sciences, and applied group, at type of liquid being moved can dramatically influence the accuracy Agilent Technologies (Santa Clara, CA), says, “Lipidomics and of the liquid transfer at different transfer volumes,” Edwards explains. metabolomics studies generally work in the milliliter range, while “For example, nanoliter transfers of glycerol won’t be handled as

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easily or as accurately as waterbased reagents.” With the right liquid-handling platform that’s running in top form, you can transfer lots of low volumes at high levels of performance. Hudson Robotics (Springfield, NJ) concentrates on technology that transfers volumes down to low microliter quantities. At all volumes of How to find the right liquid handler for your liquid transfer, though, how it gets done affects the outcome. “We have application found that slight differences in technique can make all the difference,” says Alan H. Katz, chief scientific officer at Hudson. “For example, By asking you a few simple questions, our Automated Liquid many people use a pre-aspiration of air followed by a blowoff to Handling Product Finder helps you narrow down which instruments maximize accuracy, but at low volumes, this can be a problem.” He best suit your needs. adds, “When there is air in your system and you press your plunger, you are competing between releasing liquid and compressing air. All sorts of factors come into account—for example, the exact geometry Find Here of a particular tip, how wet or dry it is, how deeply it sits in the liquid—and the results can randomly vary, and are often not what you are looking for.”

Other factors impact the results as well. “We have also found that precision of low-volume pipetting is improved by over-aspirating and returning some of the liquid to the source before going to your destination. This minimizes effects from backlash,” Katz explains. “Our SOLO automated pipettor is designed to take these factors into account.”

Low volume, high throughput

Scientists and technicians don’t only go to low volumes to save sample, because sometimes they use such volumes to quickly process many samples. “Some researchers work in the world of 96-well , which hold up to roughly 300 microliters of liquid,” says Katz. “When they add ‘small’ quantities of reagents, they are usually talking about single-digit microliters.” He adds, “High-throughput screening groups that use high-density microplates, like 1,536 wells and beyond, can barely fit a microliter into a well, so they focus on nanoliter volumes.”

To work with such small volumes, two statistical factors become extremely important. The first is precision, and a lab manager should know a device’s coefficient of variance. Accuracy— transferring the intended volume—is also key. As Katz points out, “You can be very precise but have lousy accuracy—like trying to hit the bull’s-eye and always missing in exactly the same spot, like hitting dead center of the ‘20’ on a dart board.”

To get precision and accuracy, a scientist must rely on the liquid- handling supplier. “It’s important to make sure your equipment is well calibrated so precision and accuracy are optimized,” Katz recommends.

Also, you might want a platform that provides lots of flexibility. As an example, Edwards says, “Our Bravo is a versatile and flexible platform for a wide range of tip heads that can handle single to 384 tips with transfer volumes of 500 nanoliters to 250 microliters.”

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Product Focus: S-Pipette S2 S2 offers control at your fingertips with an easy-to-use interface via Microsoft Surface Tablet™. Wi-Fi capability lets you operate S2 from outside a – no external computer needed!

The motorized elevator raises / lowers plates (or reservoirs) to desired pre-set height. Add a 2-, 3-, 4-position shuttle and configure an instrument that matches your needs.

Interchangeable cores provide automated pipetting into all wells of a 96-well plate with the 96 core, or into all wells of a 384-well plate with the 384 core.

Automated liquid handling eliminates the tedium and potential repetitive motion injuries associated with hand-held pipetting.

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10 Common Liquid Handling Errors & How to Avoid Them When pipetting, operator error is often the greatest source of variation. However, with care and proper training, many pipetting errors can be quickly overcome.

While automated liquid handling systems offer greater reliability and reproducibility as they eliminate operator errors, they are not immune to error. In fact, their inherent complexity means there is still an opportunity for errors to develop in the system.

Learn more about sources of liquid handling error, and how to avoid them.

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The Latest in Pipette Tip Design "That tip you discard after each pipetting step, costing just a few cents, embodies technical sophistication that’s critical for pipetting accuracy." Brian Perry, PhD.

By Angelo DePalma, PhD

Minimum compositional requirements should therefore include inert polymers that withstand chemical challenges, gamma- and electron beam-radiation, and autoclaving. Tip polypropylene should possess sufficient clarity to allow sample visualization, and sufficient suppleness to facilitate accurate touch-off during dispensing. With typical draw/dispense volumes in the microliter range, molding quality, physical integrity, and uniformity become critical for accurate, reproducible liquid movement within the pipette tip.

Margin of error

Jon Harkins, product manager for consumables at INTEGRA Biosciences (Zizers, Switzerland), observes that for pipette tips, fit dictates function. The company’s GripTip design, used in all its Pipette tips appear to be technically simple, almost commoditized, pipetting systems, mitigates tips loosening, leaking, and falling off. yet their design and manufacture require significant thought and engineering. “That tip you discard after each pipetting step, costing GripTips incorporate a “positive stop” that causes pipette tips to load just a few cents, embodies technical sophistication that’s critical for to exactly the same height. “With generic pipette tips, if you load too pipetting accuracy,” says Brian Perry, PhD, senior product manager at aggressively the tip ejects with difficulty,” Harkins says. Generic tips Rainin Instrument (Oakland, CA). expand when loaded and fall off to return to their original shape.

Some liquid handling applications demand purpose-driven pipette Tip height is critical, particularly in multichannel pipettes and devices tips with features like low retention or binding, used for high-viscosity where 96 or 384 tips are expected to draw and deliver precisely the liquids containing sugars or glycerin or highly concentrated salts. same volume. Tips seated too high on a pipette tip fitting may not reach fluid level and thereby aspirate air. Failing to make contact when Exquisite engineering notwithstanding, no pipetting system performs touching off during dispensing causes liquid to remain within the tip. reliably if the tip discharges contaminants during operation. Slip Affected wells become dead points. agents, which are chemicals employed during the manufacture of injection-molded plastic parts to enhance manufacturability, are These problems are magnified with today’s ultra-lowvolume one potential contamination source. Tips not manufactured under pipetting. The volumetric margin of error shrinks when dispensing pristine conditions and thoroughly inspected may harbor adventitious 0.2 microliters compared with 500 microliters. “In many cases, all biological or chemical contaminants as well. For plastics, of which you’re pulling and delivering is a drop delivered at touch-off,” Harkins tips are made, leachables and extractables may affect data fidelity and observes. “If your tips are not perfectly straight and aligned at the experimental results in insidious ways. same height, that drop will remain in the tip.”

“Even tips free of any detectable superficial contamination may Contamination and carryover release leachables if their materials of construction are poorly formulated,” Perry adds. Buffers, salts, acids, bases, and organic Contamination and cross-contamination are perennial issues in chemical constituents may initiate leaching of residual monomers, pipetting, says Karla Mantia, global product manager for pipette tips at polymerization agents, or even metals. Thermo Fisher Scientific (Pittsburgh, PA). “Pipetting creates aerosols

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of the pipetted sample that are suspended in the air space inside pipette itself,” Mantia adds. Aerosols and liquids introduced through the pipette tip between the drawn liquid and the pipette nose cone.” over-pipetting can eventually cause corrosion or compromise seals. Absent some sort of barrier, aerosols enter the pipette, remain inside, This is more likely to occur over time if the user fails to clean and and carry over to subsequent samples. Cross-contamination occurs as service the pipette periodically, and leads to physical deterioration and previously aspirated air is dispensed along with the sample. loss of accuracy.

Many highly sensitive reactions will yield erroneous results in the The degree of protection depends on the filter/barrier type. presence of contaminants; for example, polymerase chain reaction Eppendorf offers standard Dualfilter T.I.P.S.® that provide aerosol (PCR). The list of PCR inhibitors is long: bile salts, urea, and calcium protection but allow samples to draw beyond the barrier if liquid is ions, to name a few. accidently over-pipetted. The company also sells tips that seal off on contact with liquid to prevent liquid from rising above the barrier. Filtered pipette tips prevent aerosols from reaching the innards of the pipette and carrying over to the next liquid transfer. Several Customization is rare in the pipette tip world outside of packaging. filter and barrier designs are available, constructed from different Tips normally come in a rack of 96 but customers sometimes ask materials and each with specific effectiveness related to contamination for packages of ten or 20, or even individually packaged tips. These control. “Where filtered tips keep aerosols from entering the pipette, are useful for clean room processes where workers bring in only the a self-sealing barrier keeps out liquids as well, providing superior materials and equipment they need. Over the years, manufacturers protection,” Mantia says. of pipettes and pipette tips have improved products to make manual liquid handling easier and more ergonomic. While welcome, Filter tips prevent contamination of the pipette and sampleto- sample innovation has produced a somewhat chaotic marketplace. cross-contamination. DNA/RNA applications often employ these tips to mitigate the activity of DNases and RNases, enzymes that An ISO standard, 8655-2 recommends that customers should hydrolyze nucleic acids. use pipettes and tips from the same manufacturer, even for “open system” products. Hager explains that no industry standards exist for “Customers working with viruses should also consider filter tips to dimensions of nose cones or tips drawing specific volumes. “But when avoid transferring potentially pathogenic agents from virus stocks to you purchase a pipette from a manufacturer that also sells the tips, the cultured cells,” says Kayla Hager, product manager for consumables pipette is calibrated for that specific tip. Using another supplier’s tips at Eppendorf (Hauppauge, NY). Filter tips are also appropriate requires recalibration.” for manipulation of radioisotopes, which many labs still use due to legacy methods or the unavailability of appropriate fluorescent labels. Anyone who has ever worked with radionucleotides recognizes how easily surfaces—even those that seemingly do not come into contact with radioactive materials—become “hot.” Counts transferred from one experiment or process to another are result-destroyers.

Protect the pipette

In a filter-fitted tip, a barrier exists between the nose cone of the pipette and the liquid draw region of the tip. The design must allow airflow, however, or aspiration will not occur. The filter catches aerosolized particles like aqueous droplets, DNA, or virus particles. Tips are mostly made of polypropylene, but filter composition varies among manufacturers.

Filter and barrier tips cost more than their unmodified counterparts based on materials, design, and manufacturing. The increment is small, however, compared with the cost of reagents, buffers, time, and labor associated with rework due to contamination, or pipette repair or replacement. These factors alone justify the use of barrier tips.

“Sample contamination aside, one must consider protecting the

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Featured Manufacturers

Apricot Designs

Apricot Designs specializes in purpose-built equipment providing innovative, accurate, and precise liquid handling technology that reflects the increasing complexity and requirements of biotech, clinical, and pharmaceutical research.

As liquid handling experts and specialists in multi-channel micro-volume pipettors, disposable pipette tips, and high-performance evaporators, we focus on the lab automation needs of researchers, scientists and lab professionals worldwide with equipment designed to make lab work more accurate, more precise, more efficient and thus, more productive.

www.apricotdesigns.com/products.htm

BrandTech

BrandTech’s liquid handling line, which includes the Transferpette® pipettes and HandyStep® repeating pipettes, BRAND Dispensette® bottletop dispensers and Titrette® bottletop , is distinguished by the accuracy, precision, safety, and ergonomics of the instruments’ designs. The BRAND Life Science Plastics line includes their innovative line of disposable UV- that allow photometric measurements down to 230 nm and fit nearly all spectrophotometers. The line also includes 96-, 384-, and 1536-well plates; PCR tubes, strips, plates and mats; and microcentrifuge tubes. BrandTech® now also exclusively offers BRAND’s Class A, USP Certified volumetric glassware, which provides the highest degree of technical perfection for consistent, precision analysis. www.brandtech.com

Biotix

Innovation is at the heart of Biotix Engineering. Our product development starts with questions. How can we develop a product that enables researchers to achieve more accurate and precise results? How can we shorten the time between question and answer? How can we engineer products to use less resources? How can we drive this innovation across our industry and beyond to make a significant and overwhelmingly positive impact.

www.biotix.com

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Featured Manufacturers

Agilent Technologies www.agilent.com

Art Robbins Instruments www.artrobbins.com

Beckman Coulter www.beckmancoulter.com

Eppendorf www.eppendorf.com

Hamilton Company www.hamiltoncompany.com

Hudson Robotics www.hudsonrobotics.com

INTEGRA Biosciences www.integra-biosciences.com

Rainin Instrument www.rainin.com

Tecan www.tecan.com

Thermo Fisher Scientific www.thermofisher.com

TTP Labtech www.ttplabtech.com

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