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August 01, 2010 (Vol. 30, No. 14)

Refining Automated Liquid Dispensing

New Instrumentation Aims to Make Process More Accurate and Reproducible

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    Compatible with 19 interchangeable pipetting heads, the Thermo Scientific Versette provides versatility, from single- to 384-channel automated pipetting.

    High-throughput screening (HTS) has allowed researchers to conduct large-scale biochemical assays for the rapid identification of active compounds, antibodies, or genes of interest. In order to ensure that potential drug candidates are accurately identified, with minimal off-target effects, high-throughput assays are incorporated as the starting point for drug design, as well as to provide a deeper understanding of various intra-cellular and cell-cell interactions.

    With the ability to screen a wide range of static assays against a comprehensive library of candidate compounds, HTS provides a means of identifying and analyzing cellular events, including kinase activation/inhibition, up/down regulation of signal transduction pathways, and apoptosis. The assays that are incorporated into any one screening campaign are dependent on the therapeutic targets, which can include cancer, cardiovascular disease, and inflammation. However, for any assay, a precise and accurate method of liquid dispensing is essential to reduce the chances of incurring any potential error.

    The need for accurate dispensing of liquid volumes has ensured that multichannel liquid dispensers have become a mainstay in the majority of drug discovery laboratories. Such liquid transfer is often used in the dilution of concentrated stock solutions, which will subsequently be dispensed across the assay plate for analysis. However, there is the potential for error when creating any dilutions, as well as when dispensing compound solutions into the assay plate, which can propagate into false positive or negative results in the initial screen. 

    With additional uses in the pharmacological proofing of compounds, liquid-handling instrumentation has the capability to accurately perform repeated dispensing, mixing, and aspiration cycles in successive wells. The resulting drug titrations or dose-response curves can then be used to determine the potency of the drug candidates during the primary screen. Accuracy is, therefore, key in the creation of these dilution series to ensure that the most potent compounds are selected and moved forwards for further analysis, minimizing the time required for hit-to-lead and lead-to-market.

    Due to the minute volumes typically handled during HTS, most commonly on the microliter scale, inaccuracies of just 1 µL can have an adverse effect on experimental integrity through the production of false positive or negative results. Although this is not detrimental to experimental data, false positives can significantly reduce laboratory efficiency.

    Minimizing the number of false positives incurred will, therefore, aid in the reduction of unnecessary re-tests, while minimizing reagent loss. In addition, false negatives can lead to lost opportunities and the need for more regular and extensive re-testing to identify any potential lead compounds, which have been missed.

    In order to ensure that dispensed volumes are highly accurate, we investigate the dispensing precision of microliter volumes using the Thermo Scientific Versette liquid-dispensing automation platform from Thermo Fisher Scientific (Figure). Performance was validated across a wide volume range using a single-, 8-, 12-, and 96-channel pipetting head to ensure accuracy and precision over the instrument’s complete capability range.

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