Liquid handlers are essential in drug discovery but have been prone to limitations inherent in their design. As researchers miniaturize to reduce cost and allow the use of rare reagents and cells, these limitations can become more serious. Significant limitations include transfer accuracy, transfer precision, cross-contamination, binding, leachates, damage to transferred material, errors associated with surface tension and viscosity and running costs.
Acoustic liquid handling, as embodied by the Labcyte Echo liquid handlers, addresses all of these short-comings. A pulse of focused sound energy ejects a droplet of precise volume from a source—usually a multiwell plate. Individual droplets are ejected as rapidly as 500 times per second to facilitate large volume transfers. Prior to ejection, a gentle pulse of acoustic energy interrogates each sample before ejection by disrupting the fluid surface of the source. By monitoring the echoes of the interrogating pulse, the Echo system automatically adjusts the energy to ensure precision and accuracy across fluids as diverse as media with surfactants, solvents, solutions of polymers and 50% glycerol. Typical coefficients of variation (CV) for transfers are less than 4% even at low nanoliter volumes.
Disposable tips and cartridges can generate false positives from cross-contamination left after multiple washes as well as from biologically active compounds leached from disposable tips. Because nothing physically touches the fluid with acoustic transfer, cross-contamination and the impact of leachates is reduced.
Absorption of compounds to pipette tips and microplates during serial dilution appears to be a significant problem. AstraZeneca reported that dose-response results varied depending upon the type of liquid handler and dilution method. Compounds appeared hundreds of times less active when processed by traditional methods. X-ray crystallography showed that results generated from acoustic transfers more closely described an enzyme-binding site than did results from serial dilutions achieved with automated pipettes.
During liquid handling, components damaged by traditional techniques are untouched by acoustic methods. Shear stress may damage or lyse cells as they squeeze through the bore of a pipette tip. The low energy levels of acoustic transfers eliminate lysis. Likewise, proteins and nucleic acids are not damaged. Piezo-driven liquid handlers denature proteins with heat while Echo systems transfer at ambient.
Liquids in biological sciences differ in physical properties. A surfactant can dramatically drop surface tension. Low surface tension can rapidly drain out of pipette tips and affect transfer volume with pin-tools. Meanwhile, some liquids are viscous, making them difficult and slow to pipette. Since acoustics automatically determine the energy required for transfer before ejection, excellent results can be obtained even with solutions of high and low surface tensions and high and low viscosities in the same multiwell source plate.
Finally, although individual tips are inexpensive, costs accumulate especially when disposal costs of tips and wash solutions are included. Acoustic liquid handling allows for easy miniaturization of assays, which reduces costs, and saves further as it eliminates tips. Moving from a 96-well to a 384-well format can reduce the cost per well by 75% and a 1536-well format can reduce costs by almost 94%.