A guide to automated liquid handling systems for the high-growth cell culture market.

The Hamilton STAR workstation is designed for cell culture and maintenance. Images: Hamilton RoboticsStem cell research has been breaking ground in new application areas over the past few years, and it’s poised for even greater growth as more companies and organizations realize the potential. In the next decade, cell-based therapies will become increasingly common for cancer, immunological disorders, cardiac failure and other conditions.

According to BCC Research, the global market for stem cells was $3.8 billion in 2011 and could reach $6.6 billion in 2016, reflecting a five-year compound annual growth rate of 11.7%.

Many laboratories, however, still use manual cell culture processes that are time consuming, labor intensive and prone to error, creating a bottleneck for commercialization and potentially life-saving treatments. For these therapies to become widely used, live cell-based production methods must be standardized and automated to provide large numbers of high-quality cells and enable large-scale clinical trials and commercial production.

Market snapshot
The cell-based assay segment of laboratory automation currently accounts for approximately 25% of automated systems used for liquid handling robotics. Within this segment, the most common applications for cell culture automation include cell line development for monoclonal antibodies (mAb), cell production, induced pluripotent stem cell (iPSC) research, cryobanking, cell-based assays and cellular expression. All of these applications require routine cell maintenance and culture.

To meet this demand, equipment manufacturers have developed fully automated, end-to-end systems with a wide range of options and accessories. Adapting a bench protocol to automation takes effort and is no small undertaking. Most laboratories would benefit significantly from consulting an expert to help guide the process. When choosing a system, the many laboratories that have already made the switch found that the most critical factors are ease of use, standardization, flexibility, throughput and walk-away time.

Automation basics
For cells to grow in culture, automated systems must maintain very tight control over multiple growth parameters. For example, they must be able to maintain a sterile and comfortable environment, ensure appropriate nutrients and maintain cell numbers and confluence. When evaluating platforms, laboratories must consider the combination of equipment that controls these parameters, including their interaction with each other, to form a cohesive solution.

Media fill module can deliver warmed media to the pipetting workspace.Typical system components
Liquid handlers
Central to any automated cell culture system is the liquid handler, which must perform a range of tasks, including interfacing with equipment such as incubators and imagers. It’s crucial that laboratories evaluate the mode of pipetting and sterility associated with this process, and investigate how the liquid handler maintains and moves cells during plating, passaging and harvesting. One system particularly well suited to cell culture automation is the Microlab STAR workstation by Hamilton Robotics. This system, designed after spending time in laboratories with customers, makes it easy to perform the many complicated steps of cell culturing.

Automated pipetting
Also critical to choosing a cell culture automated system is the mode of pipetting. Using high-performance air-displacement technology is ideal. Systems that use liquids and self-contained liquid channels pose a greater risk for contamination. It’s also important to evaluate the dynamic pipetting range for assay flexibility, as well as the disposable tip attachment technology to ensure the best tip seal.

Automation software
Cell culture automation requires sophisticated operating and data tracking capabilities, and a platform’s software can severely limit or dramatically enhance its capabilities. When evaluating automated platforms, laboratories should make sure that the software enables users to program scheduled workflows and to select cell culture plates for particular processes, such as cell plating or adding growth factors. The best systems have software that provides maximum traceability, including a full “plate trail” listing all steps that each plate has undergone.

Required accessories
A standard liquid handler needs a variety of additional components to plate cells, exchange media and passage and harvest cells.

Cell suspension
Researchers often start an experiment with assay-ready cell plates of batches of cells from a single suspension, which often settles. Cell suspension modules keep large batches of cells continually in suspension for high-throughput plating experiments, saving time and improving cell viability.

Heater shaker module for heating and assisted adherent cell passaging.Media fill modules
Automated cell culture systems also require large volumes of fresh media from a sterile source container to be delivered to the pipetting platform when performing media exchanges. Media fill modules, such as the one offered by Hamilton Robotics, can deliver warmed media to the pipetting workspace through a disposable fluid path connected to a source container (4 C) located off-deck.

Containment devices
To maintain clean air over the workspace and protect sterile cell cultures, manufacturers offer a variety of hoods. The best are HEPA-filtered hoods that connect directly to the liquid handler. Ideally, a liquid handling platform also integrates with biosafety cabinets for additional protection.

Integration with third-party devices, such as incubators, is important for a fully automated, end-to-end, cell-based production system. Incubators control important parameters of cell growth by maintaining proper growing temperatures, pH control and humidity. These devices also offer decontamination routines and can accommodate many different sample capacities and sample formats (tube or plate).

Automated cell counting saves time and is necessary for large-scale, cell-based production systems. Cytometers easily integrate with high-quality liquid handling platforms and are critical in monitoring cell health and viability, and in determining cell confluence, which indicates when to passage cells.

Other accessories include tilt modules that enable complete media and cell removal during aspiration steps for passaging and harvesting, and heater shakers that assist in dissociating adherent cells from culture vessels.

Cell culture automation increasingly instrumental
With the increasing use of live cells for biological research, therapies and drug discovery, automated cell culture systems are becoming even more instrumental in solving the large bottlenecks associated with manual cell culture practices.

These newer application-based systems can completely control and track all cell culture processes, increase throughput and reduce labor costs, all while further enhancing researchers’ ability to understand and treat disease.