Automated liquid handlers (ALHs) are one of the truly enabling technologies of modern life sciences, particularly in medical testing, biological research, and high high-throughput screening. Applications in combinatorial chemistry and materials investigations were considered emerging a decade ago, but these markets remain small.
Liquid handlers use robotically controlled pipettes to deliver precise quantities of liquid reagent to reaction vessels, more often than not to microtiter plates. Major instrument manufacturers include Beckman Coulter, Tecan, PerkinElmer, Eppendorf, QIAGEN, and the two firms interviewed for this article.
“Automated” is the functional word in ALH markets. Once a method is entered, robots are expected to deliver fluids continuously and precisely (both in terms of location and quantity), with extremely high reproducibility, often nearly continuously.
Simplicity but not simplistic
Manufacturers of ALHs are feeling pressure to simplify, to offer products that resemble workstations rather than stand-alone instruments. “That doesn’t mean they want simplified capabilities,” says Isaac Meek, technical specialist at Caliper Life Sciences (Hopkinton, MA). “They want the features and functions, but they also want to be productive without having to be programming experts.”
Caliper and other vendors therefore “encapsulate” or standardize methods to liquid handler configurations, thus multiplying the instruments that can benefit from specific methods. Users need only dial up the method and apply it to their workflow, without investing a lot of effort into becoming an automation or methods development expert. “Nobody wants to become intimately familiar with details like those,” Mr. Meek says. “We see demand for this from several corners of the industry, including genomics, proteomics, and compound management.”
Another significant trend, according to Mr. Meek, is shrinking instrument size and discrete systems rather than complex, cobbled-together devices reaching across an entire lab. “Users want desktop-sized instruments that will not interfere with other equipment.” With more-compact footprints have come software improvements that positively affect usability.
Users increasingly look for true walkaway automation, a capability that, according to Mr. Meek, has been often touted but rarely delivered. Increasingly, instruments can handle complex operations without human intervention and send a text message to indicate that the job is complete.
All these benefits are a result of a common factor in lab instruments: the disappearance of the instrument specialist. Organizations used to have core mass spec or microscope facilities. “Those days are gone,” says Mr. Meek. “Now we’re seeing a genomics core consisting of several pieces of high-tech instrumentation, where workers are expected to be familiar with several instruments. We’ve gone from an instrument or methods focus to an application focus.”
Another important trend, which first became prominent during the high-throughput screening era in pharmaceuticals, is the ability to track and monitor samples as they wind through the workflow. “This began with screening, then became common in genomics, and now it’s everywhere.”
Pipetting accuracy and calibration, which go hand in hand, are significant operations or features, depending on one’s perspective, in automated liquid handling.
Calibration is usually done gravimetrically, but the weakness of this approach is that by weighing the entire plate (the standard method) one obtains the average volume delivered but no inkling of tip-to-tip variability.
“When we introduced our first liquid handler in 1990 for emerging high-throughput screening applications, there was greater concern for coefficient of variation than for absolute accuracy,” says Tom Astle, president of Tomtec (Hamden, CT). “Users wanted and expected all samples to be the same. Today, with the emphasis on bioanalysis, accuracy is king.”
Issues in delivery accuracy vary depending on the type of displacement used. Air displacement, which uses disposable tips, creates the most pipetting variation, according to Mr. Astle. “Depending on how the tips are made, you can have considerable variation, depending on whether the tip surfaces wet or not and how much liquid clings to them.”
With positive displacement pipetting, the piston plunges to the bottom of the tip’s orifice, so there is no air gap or dead air volume that can affect dispensing. Positive displacement delivers superior tip-to-tip reproducibility, Mr. Astle says, but by necessity it requires tip cleaning, another possible source of error.
Mr. Meek mentions three factors that potential buyers should consider when shopping for an automated liquid handling system:
- Software versatility and ease of use: How easy is it to learn? Does the instrument come with useful software content or methods? How steep is the learning curve?
- Instrument size and configuration: Liquid handlers should not require special tables or space, or dedicated hoses or power supplies.
- Flexibility, expandability, and ability to integrate with other systems if needed. These benefits are important if labs expect increased throughput needs or if methods change.