Lab Automation Trends
Since the introduction of the 96-well microplate, there
has been an ongoing trend towards miniaturization. The first implementation
was in the form of the 384-well plate. Increasing the capacity of the
original by a factor of four brings many advantages in the form of higher
throughput capability and less usage of sample, solvents, and reagents. The
384 density is achieved within the same external dimensions as the original
96-well microplate by reducing the size of the individual wells. This
impacts almost any microplate-based device that is used to automate
processes based on the 384-well format. Liquid handlers must be able to
pipette accurately and reproducibly into the smaller wells, washers and
dispensers must also be able to handle that format, and readers must be able
to perform their detection as well. Robot grippers can handle the 384-well
plates since the external form factor is the same, but in many cases more
accurate positioning of the plate is required on the target device because
of the smaller wells and higher density of wells. Most of these issues have
been overcome, and the 384-well format is becoming the norm in high
throughput screening.
This trend is being continued with even higher
densities. The 1536-well plate is seeing more common use, and while keeping
that number within the same external dimension produces a density that
stretches the ability of liquid handlers and other devices, even higher
densities are being developed. The trend is to screen ever higher numbers of
samples, leading to the term UHTS, or Ultra High Throughput Screening,
referring to the analysis of >100,000 samples per day.
Throughout the history of Lab Automation, a large
variety of microplates have been designed and sold to meet the various needs
of HTS. The microplate is an entire, complex industry in its own right. Not
only are there many types of plates in terms of physical characteristics
such as composition material, well shape, well depth and transparency, there
are also many plates that have been precoated with the various chemicals or
reagents that are required for various assays. With a lack of
industry-agreed-upon standards, there has been variability in the dimensions
of these microplates. This can lead to difficulties in plate handling for
the various devices that are being used. For this reason, users and vendors
are agreeing to a predefined set of dimensions for the microplate format,
which will lead to increased reliability and flexibility for Lab Automation
systems. The Microplate Standard initiative is being led by the Society for
Biomolecular Screening, (SBS).
The trend towards the denser microplate formats means
that ever-higher numbers of samples can be screened. While each process has
unique on the time requirements, automated systems or workcells operating 24
hours a day can process several hundred microplates in day.
Process 200 plates/day:
96-well = 19,200 individual analyses
384-well = 76,800 individual analyses
1536-well = 307,200 individual analyses
ASRS
Each HTS library represents valuable intellectual
property and holds within itself the potential hits that represent future
drug candidates. The libraries themselves need to be managed in an automated
way in order to effectively continue ongoing screens. Since the library
compounds need to be stored while they are awaiting the next screen, and
retrieved for each screen, this operation is referred to as Automated
Storage and Retrieval, or ASRS.
ASRS systems for drug discovery libraries have a
history that parallels that of lab automation. In this case, the library
compounds can be stored in the ubiquitous microplate format, but it is also
common for some type of tube to be used. The tube-based system will require
liquid-handling automation at some point to transfer the compounds from the
tubes into microplates for the screening.
Compound libraries range in size from 10,000 compounds
to > 10 million. The storage format greatly influences the design and scale
of the ASRS system. For example, if compounds are stored in vials, then a
100,000 compound library would require 100,000 individual vials to be
stored. In comparison, less than 300 384-well microplates could be used to
store 100,000 compounds. Some companies have developed proprietary libraries
that can store multiple tagged samples within an individual tube, allowing
further increases in density.
There are
2 major pieces to consider for an ASRS: The storage and retrieval system
itself, and automation robotics outside of the system that serve to link the
compounds with downstream processes. These include liquid handling
operations to transfer aliquots from mother to daughter plates, or to
perform tube-to-plate transfers.
Many of the early ASRS systems
were designed and built by specialized lab automation vendors. The hardware
and software components were built from industrial robots and placed into
large-scale systems that were very expensive and required long timelines to
fully implement. As in lab automation in general, there is a trend toward
more modular, simple, fast, and economical solutions for ASRS systems.
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