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Automated Low Volume Dispensing Trends

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John Comley

Most end-users familiar with automated liquid handling regard dispensing in the nanoliter (nL) to picoliter (pL) range as low volume. It is generally accepted that such volumes are beyond the range of most conventional air displacement pipettors, which have a reliable lower dispensing limit of around 0.5µL (500nL). Such conventional systems for the most part rely on contact dispensing i.e. they require surface tension (touch off on destination plate) to remove the drop from the tip or dispensing element. In contrast, the majority of low volume dispensers (LVD) use non-contact dispensing i.e. they rely on force to eject a drop from the dispensing element and do not require contact with the destination surface. Some of the main technologies used in today’s automated LVDs include: syringe pumps; positive displacement micropipettes; solenoid valves with either syringe pump or pressurized line; capillary sipping; pin tools; acoustic droplet ejection (ADE); acoustic activation; piezo-actuated (based on glass capillary/steel tube, print head or other design); and inkjet cartridges. 

Factors that become much more important when dispensing nL to pL volumes include: mechanical tolerances; liquid compressibility; susceptibility to clogging; tip orifice uniformity; viscosity; instrument calibration stability, and not forgetting the surface chemistry, which is beyond the control of the dispenser. 

Historically the initial market for LVD was in diagnostics and genomics, mainly around microarray, biochip and biosensor creation and first utilized pin tools later to be superseded by piezo-actuated dispensers. Applications in sample management typically in DMSO solutions (e.g. compound reformatting, cherry picking and dose-response analysis) then came to the fore, with non-contact syringe-pump dispensers and capillary sipping technology initially favoured, although both now are largely replaced by ADE. More recently miniaturized bioassays in aqueous solutions (e.g. qPCR/sequencing, HTS assay setup and cell-based screening) have come to rely on LVD using solenoid-valve based bulk dispensers, positive displacement micropipettes and ADE. Other niche applications like protein crystallography and MALDI target loading have largely favoured positive displacement micropipettes and capillary sipping; whilst combination screening has recently been exploited by inkjet cartridges and ADE. 

In March 2016 HTStec undertook a market survey on automated LVD mainly among research labs in pharma, biotech and academia. The survey was initiated by HTStec as part of its tracking of emerging life science marketplaces and in some aspects updates HTStec’s earlier report on the subject published 10 years ago. The questionnaire was compiled to meet the needs, requirements and interests of the automated liquid handling vendor community and of manufacturers/developers of new low volume (nL to pL) dispensing technology who wish to gain a better understanding of the current and future market requirements for fully automated LVD systems. This article contains ‘selected findings’ from the HTStec market report, ‘Automated Low Volume Dispensing Trends 2016’. It is intended to provide the reader with a brief insight into recent market trends. It covers only 11 out of the 30 original questions detailed in the full report. The full published report should be consulted to view the entire dataset, details of the breakdown of the responses for each question, its segmentation and the estimates for the future. Please click here for more information.

Preferred technology approach to LVD:


Figure 1. Preferred Technology Approach To Low Volume Dispensing

The preferred technology approach to LVD are detailed in Figure 1. This showed that the preference was equally shared between ADE and n/a- no approach preferred. This was followed by syringe pump; positive displacement micropipettes and then solenoid valve with pressurized line. 

Most used dispensing range in an LVD system:


Figure 2. Low Volume Dispensing Ranges Used Or Wanted 

The dispensing range most used in an LVD system by survey respondents are given in Figure 2. This showed that 0.5µL to 100nL was the most used range today. This was followed by 100nL to 5nL; 5nL to 250pL; and then 250pl to 10pL. 

The minimum droplet size wanted for LVD applications:


Figure 3. Minimum Droplet Size Required For Intended Low Volume Dispensing Applications

The minimum droplet size most wanted by survey respondents for their intended LVD applications are presented in Figure 3. This showed that the minimum droplet size was widely distributed across the range. There was however, a marginally greater preference for 5nL and 2.5nL,  this was followed by >100nL, and then 1nL and 100nL. 

The dynamic range wanted in the same automated LVD system:


Figure 4. Dynamic Dispensing Range Wanted In The Same Automated Low Volume Dispensing System

The dynamic dispensing range most wanted in an automated LVD device (i.e. the same system) are reported in Figure 4.  This showed the most wanted dynamic dispensing range to be 3 logs (e.g. 10µL to 10nL), this was closely followed by 2 logs (e.g. 10µL to 100nL).  In a separate question most survey respondents thought it was highly desirable that an LVD had a very wide dynamic range (i.e. at least 4 logs). 

The fluid types most frequently used with an LVD:


Figure 5. Fluid Types To Be Used Frequently With A Low Volume Dispenser

The fluid types to be used most frequently with an LVD are presented in Figure 5. This showed that aqueous was the fluid type to be most frequently used with an LVD followed by DMSO; protein; cells; and then DNA. The fluid type least used by respondents was oils. 

The importance of avoiding disposable tips and tip washing in an LVD workflow:


Figure 6.  Importance In Low Volume Dispensing Workflow To Avoid Disposable Tips & Washing

The importance in respondent’s LVD workflow to avoid disposable tips and washing are given in Figure 6. This showed that most (49%) of respondents thought it was highly desirable to avoid disposable tips and washing in an LVD workflow (i.e. to have the ability to dispense/eject samples, as enabled by ADE on the Labcyte Echo). This was followed by nice to have (23%); and absolutely essential (must have) (19%). Leaving just 9% who thought it was not needed. 

Most needed LVD technology:


Figure 7. Low Volume Dispensing Technology Most Needed For Respondent's Applications 

Details of the LVD technology most needed by survey respondents for their dispensing applications are shown in Figure 7. This showed that respondent’s main priority was non-contact dispensing (40%). This was followed by acoustic droplet ejection (ADE) (25%); bulk reagent dispensing (13%); drop-by-drop dispensing (step and repeat) (9%); and then contact dispensing (8%). All other LVD technologies were of minimal need to respondents.

Broad application area of LVD:


Figure 8. Broad Application Areas Of Low Volume Dispensing Of Most Interest To Respondents

The broad application area of LVD of most interest to respondents are presented in Figure 8. This showed that there was greatest interest in miniaturized bioassays, with 66% of respondents interested. This was followed by dose-response (53%); cherry picking (47%); compound management (45%); and then combination screening (38%). All other application areas of LVD had only limited interest among respondents. The specific application area of LVD of highest priority interest to survey respondents was dose-response creation of a drug dilution series from concentrate for use in a bioassay, and the setup of miniaturized bioassays either for qPCR/sequencing or HTS and screening assays. 

Main limitations of acoustic droplet ejection (ADE) technology:


Figure 9. Main Limitations To Adopting Acoustic Droplet Ejection Technology

ADE (e.g. Labcyte Echo) has emerged as a very versatile approach to LVD in recent years, yet adoption is by no means universal. The purpose of this question was to investigate the main limitations to adopting ADE technology. These results are reported in Figure 9. This showed that high cost of entry was ranked the greatest limitation to adopting ADE technology. This was followed in ranked order by need to purchase acoustically qualified plates and tubes; then lack of entry level systems; and inverting my destination plates/vessels/surfaces during ejection. Ranked least limiting was the need a lower volume dispensing capability (<1nL). 

Most important features when purchasing a new LVD system:


Figure 10. Most Important Features When Considering Purchasing A New Low Volume Dispensing System

The most important features when considering purchasing a new LVD system were ranked by survey respondents in Figure 10. Accuracy/precision of dispensing was considered the most important feature, followed by robustness, throughput and then price. Software was ranked as the least important to a new purchase. 

Most appealing vendor’s LVD systems:


Figure 11.  Estimated Supplier Share Of Low Volume Dispensing Systems Market

Respondents were asked which vendor’s LVD systems they currently find most appealing from a purchasing perspective in the near future if they had a budget. The results (purchasing preferences) are presented in Figure 11 as a supplier share of the LVD systems market. This estimated the supplier share as follows: 20% Labcyte; 17% Thermo Scientific; 12% TTP Labtech; 6% Tecan; 6% EDC Biosystems; 6% BioFluidix; 5% Beckman. All other suppliers had less than 5% share. Please note this should NOT be regarded as a true market share projection. It is based on the main suppliers of LVD systems that survey respondents are most interested in purchasing an instrument from in the near future, not on the actual $ spent with each supplier. 


The selected findings reported above have shown that the preferred technology approach to LVD was either ADE or no specific approach. The dispensing range most used in an LVD system 0.5µL to 100nL. The minimum droplet size most wanted was 5nL and 2.5nL. The dynamic dispensing range most wanted in the same automated LVD system was 3 logs (e.g. 10µL to 10nL). Aqueous was the fluid type to be most frequently used with an LVD. It was considered highly desirable to avoid disposable tips and washing in an LVD workflow. The LVD technologies most wanted were non-contact dispensing and ADE. The broad application area of LVD of most interest was miniaturized bioassays. High cost of entry was ranked the greatest limitation to adopting ADE technology. Accuracy/precision of dispensing was the most important feature when considering purchasing a new LVD system. The vendor’s LVD systems which are currently most appealing from a purchasing perspective came from Labcyte and Thermo Scientific.

Over the past decade, liquid handling instruments capable of depositing fluids in low volumes with ultra-high precision and accuracy have become much more sophisticated, have realised much greater reliability and are easier to operate. Several instrument advances are worthy of specific mention: 

1) Dynamic Fluid Analysis™ enabled on the Labcyte Echo ADE dispenser,  which provides the ability to easily adapt to different types of fluids (e.g., DMSO, buffer, reagent containing glycerol, etc.) by removing the calibration requirement. Dynamic Fluid Analysis determines the appropriate transfer parameters on a well-by-well basis, and therefore works with more complex reagent sets or inconsistent reagents. This advance has been critical in enabling the Labcyte Echo to extend its capabilities beyond DMSO-based compound management into the aqueous-based screening, bioassay and genomics arena. 

2) Tecan D300e Digital Dispenser which offers a simple method for setting up PCR reactions, generating enzyme profiles, synergy experiments and dose-response curves. It utilizes HP’s Direct Digital Dispensing inkjet technology, to enable non-contact dispensing over a very wide dynamic range (pL to µL) of liquids directly into the assay plate. The system’s powerful software combines advanced experimental design with intuitive operation, allowing you to set up a wide range of experiments including synergistic (combination) studies and randomized plate layouts in minutes. This advance has facilitated the transfer of dose-response curve generation from central core labs into the hand of scientists at the bench. 

3) TTP Labtech’s mosquito Crystal has become a very popular automated LVD with protein crystallographers. With mosquito’s unique nL liquid handling technology (disposable positive-displacement micropipettes) you can use smaller volumes of precious protein samples with no risk of cross contamination. Mosquito Crystal can automate all the popular protein crystallisation screening techniques like hanging drop, sitting drop and microbatch as well as seeding or additive screening plate preparation. This advance has facilitated perfect drop formation for optimal protein crystallisation. 

4) Thermo Scientific™ Multidrop™ Combi nL Reagent Dispenser is a bulk reagent dispenser with a volume range of 50nL to 50µL. Multidrops have been the mainstay of bulk dispensing for over a decade, the Combi nL enables the Multidrop to move into miniaturized bioassay assembly. The Combi nL’s visual, icon-based on-board user interface makes setting up, using and maintaining the dispenser extremely easy. The Combi’s fast dispensing combined with full robotic compatibility ensures increased assay throughput for labs needing low volume assay formats.

As new miniaturized and nanoscale applications emerge in life science research we can expect automated LVD to play an important supporting role.

John Comley is Managing Director of HTStec Limited.

DISCLAIMER: HTStec Limited has exercised due care in compiling and preparing these Selected Findings from its Report, which is based on information submitted by individuals in respondent companies. HTStec Limited has NOT verified the accuracy of this information, nor has it is established respondent’s authority to disclose information to HTStec Limited. HTStec Limited expressly disclaims any and all warranties concerning these Selected Findings including any warranties of mechantability and/or fitness for any particular purpose, and warranties of performance, and any warranty that might otherwise arise from course of dealing or usage of trade. No warranty is either expressed or implied with respect to the use of these Selected Findings. Under no circumstances shall HTStec Limited be liable for incidental, special, indirect, direct or consequential damages or loss of profits, interruption of business, or related expenses that may arise from use of these Selected Findings, including but not limited to those resulting from inaccuracy of the data therein.