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Jun 15, 2012 (Vol. 32, No. 12)

Increasing Throughput with Automated Liquid Handling

  • Direct Dilution Strategies

    Toby Winchester, an application consultant for Titian Software, discussed his firm’s Mosaic Sample Management Software suite, which can be integrated both with standalone instruments and with integrated systems such as the Labcyte® POD™ (an automated plate handler), according to Winchester, who discussed the pros and cons of these various integration approaches (such as time to develop the software versus expertise necessary to run the process).

    In particular, he noted that Mosaic offers the options of offline and online full integration—depending on the variability of the processes being controlled.

    Offline integration is ideal for processes that are subject to frequent change (such as in an assay development environment), whereas online full integration is ideal for more developed processes not needing as high an expertise to run (as in support of safety studies). Online integration is also appropriate for processes that support more complex platforms such as Agilent’s BioCels.

    With Mosaic, a workflow is requested and machine control scripts and commands are automatically generated, so the setup of each run takes just moments. Mosaic interfaces with the liquid handlers to obtain feedback about run results, and automatically records information about inventory changes and workflow progress.

    Winchester went on to describe recent progress that has been made in addressing the complexities of modelling the dose-response fulfillment of the Echo® dispensers from Labcyte. These acoustic dispensers allow the dispensing of small volumes, down to 2.5 nL, that permit direct dilution, rather than serial dilution, to be used to develop dose-response curves. This permits error rates to be reduced to as low as 1.0% to 1.5% compared to the multiples of 10% per dispense step typically obtained for serial dilution approaches.

    However, the Echo instruments do not have the dynamic range (typically 6 logs) required by researchers using dose response to determine IC50 (half maximal inhibitory concentration) in drug discovery. Consequently, the Echo liquid handlers require the use of an intermediate plate in order to achieve the required dynamic range. The handling of this intermediate plate has been problematic in optimizing a Mosaic solution for these instruments.

    Winchester said that Titian has developed multiple solutions to manage the workflow and inventory, including the tracking of the intermediate plates, in order to drive improvements and workflow efficiencies in its customers’ substance management groups. He noted that the Mosaic Software notices and records when the Echo instrument cannot dispense a physical sample issue, such as precipitates. (See sidebar on previous page for information on Labcyte’s own new software for Echo liquid handlers.)

  • High-Precision Flow Control

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    Fluigent’s MFCS tool was designed to control up to eight channels of a customer’s microfluidic system. (1) Users enter a pressure value for each MFCS-FLEX channel with MAESFLO software. (2) MFCS-FLEX will immediately and automatically provide the requested pressures. FASTAB technology uses a pneumatic path combined with a fast regulation algorithm. MFCS-FLEX regulates the pressure from a pneumatic pressure supply. (3) By connecting the MFCS-FLEX channels to the FLUIWELL, the pneumatic pressure allows users to precisely and smoothly control the liquid flow. Each FLUIWELL reservoir includes one pneumatic pressure connection and one microfluidic output. (4) By directly connecting the FLUIWELL to an application, samples flow from the tanks to the application.

    Anne Le Nel, Ph.D., is R&D director of Fluigent, whose solutions are based on the company’s pressure-based flow technology (FASTAB™, for fast stabilization) and consist of different tools including Microfluidic Flow Control Systems (MFCS™) that are designed to independently control up to eight channels of a customer’s microfluidic system.

    According to Dr. Le Nel, Fluigent’s FASTAB technology allows fast response and settling times (less than 200 milliseconds in specific conditions), pulseless delivery, and excellent flow stability (0.1% CV) compared to what is possible with syringe and peristaltic pumps. These characteristics are distinct advantages for the Fluigent technology and also allow it to be used successfully in long-period experiments.

    In addition, she explained, the Fluigent technology provides precise pressure (within 0.1% full scale) in different pressure ranges, positive and negative (0–25 millibars, 0–69 millibars, 0–345 millibars, 0–1 bar, and 0–7 bars for the positive pressures), to meet different pressure demands and to control flow rates ranging from sub-nL/min to thousands of mL/min.

    “Our flow-control and fluid-handling solutions are suited to many different applications: droplet manipulations, cell and particle applications, and chemical applications, among others,” Dr. Le Nel noted.

    Droplets are a key tool in many microfluidic applications, and the Fluigent MFCS are especially suited to cell manipulation, Dr. Le Nel pointed out. The need of a highly stable and pulseless flow is very important when working with cells in order to avoid shear stress, cell damage, and to be able to fully control the flow of the cells (including stopping their flow). For all these reasons, the MFCS are especially adapted to cell manipulation, offering: a pulseless flow, an instantaneous control of the flow, and independent channels to stop the flow of cells anytime that is desired.

    Dr. Le Nel described Fluigent’s MAESFLO software, which works with the company’s FASTAB technology and products to enable the control and monitoring of flow with a high level of precision and short response time. This software allows complex experiments with different pressure requirements to be completely automated using the Fluigent technology. Dr. Le Nel pointed out that the MAESFLO software has recently been upgraded to provide a feedback loop between external flow sensors and the pressure pump in order to monitor and control all the flow-relevant parameters: flow rate and pressure.

  • Software Allows Auto-Adjustment of Acoustic Liquid Handling

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    The Echo liquid-handling platform uses acoustic energy to transfer liquids. Sound waves eject precisely sized droplets from the source liquid into a microplate, microscope slide, or other surface suspended above the source.

    Joe Barco, Ph.D., product manager of the Echo liquid handlers produced by Labcyte, recently talked about the company’s new software advance that reportedly enhances the capabilities of these devices.

    Echo liquid handlers transfer volumes as small as 2.5 nL by the use of acoustic energy, thus avoiding the cost and contamination risk commonly associated with other liquid-handling systems requiring the use of tips.

    The software feature is called Dynamic Fluid Analysis™ and it permits the Echo liquid-handling systems to adapt to fluid property changes such as surface tension and viscosity on a well-by-well basis, and to adjust the necessary sound energy in real time with no operator intervention required. This eliminates the operator calibration required by other liquid-handling devices.

    “Developing calibrations for liquid handlers becomes more complicated at lower volumes. Echo instruments remove this hassle,” notes Dr. Barco.

    He sees the new feature set as having particular application in sample transfers where reagents are highly variable, such as in crystallography, and in cell lysate, serum, and plasma transfers.

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