The Shift to Digitization in Cell Culture Monitoring

Cell culture is a valuable tool with numerous applications. It allows us to study the normal physiology and biochemistry of cells, explore mechanisms underlying disease, test the effects of drug compounds and manufacture biotherapeutics. The ability to continuously monitor cells in real-time ensures precious time and money is not spent conducting experiments on cells that aren’t viable. It can also help to optimize your culture conditions and identify contamination.

Technology Networks spoke to John Moore, president of Scientific Bioprocessing (SBI) to find out more about the monitoring of cell cultures in real time using optical sensors.

Kate Robinson (KR): Why is the monitoring of cell culture processes important?

John Moore (JM): Since Harrison started in vitro cell culture in 1907, few breakthrough advancements have taken place, with 3D cultures being one of the most notable. Cell culture systems such as tissue culture flasks, multi-well plates and shake flasks are essentially black boxes. Current workflows rely on manual operations such as opening the incubator for visual inspections and taking the culture vessel out for imaging, sampling or other off-line assays. These manual workflows increase human error and contamination risk, are time consuming and costly and are not effective in providing the data cell scientists need to make timely cell culture decisions.

Critical cell culture information includes signs of contamination, cell proliferation (cell counts), viable cell density, cell morphology, confluence, phenotypic expression of specific markers and intra- and extracellular protein expression. Depending on the experimental goals and application, monitoring of this information provides the data needed in testing experimental hypotheses and advancing science.

KR: How are cell cultures typically monitored and what trends are driving the shift to digitization of these processes?

JM: Cell cultures today are typically monitored off-line and through manual processes. With the exception of visual inspections for contamination and phenol red changes indicating pH shifts, the majority of monitoring and data collection takes place outside of the cell culture incubator. Culture vessels are taken to microscopes and plate readers and cell and media samples are manually collected for other offline assays.

Thankfully, recent advancements in sensing technologies, automation and data analytics along with affordability have made digitization accessible. Routine and labor-intensive tasks such as pipetting and cell counting have become automated but are still not widely used. And so the reproducibility crisis in science persists as the 2016 Nature publication noted in the “1,500 scientists lift the lid on reproducibility” survey.

KR: Can you explain how your optical sensors allow online monitoring of cell culture processes and how informatics plays a role in this?

JM: SBI has developed commercially available optical sensors for online and real-time monitoring of pH, dissolved oxygen and biomass. The dissolved oxygen and pH sensors are 3 and 5 mm in diameter, respectively, and are attached inside a culture vessel with an adhesive while a reader is positioned across the wall of an optically clear vessel material for measurements. The reader is connected to a computer for data acquisition and graphing. A fiber optic reader is also available where fiber optic cables are attached to sensors in a range of accessories: fiber optic probes that are threaded through bioreactor ports, flow-through cells for perfusion flow loops and star adaptors that are positioned alongside vessels and bioreactor walls for gathering data from the hardest to reach spots. Biomass data is obtained through backscatter measurements in a highly parallelized and non-invasive manner from shake flasks and bioreactors.

The pH and dissolved oxygen sensors are single-use, disposable and sterilizable via autoclave, ethylene oxide or gamma irradiation. They are also pre-calibrated, suitable for long-term cultures and very affordable so that every researcher can have access to real-time data about their cells. These actionable data insights truly illuminate the black boxes of current cell culture systems.

KR: What are the benefits to real-time monitoring of cell cultures?

JM: Real-time cell culture insights are the foundation for closed-loop control and automation. These insights are then needed for process optimization, reproducibility, and cost reduction that, when taken together, help with high throughput testing. Real-time monitoring reveals issues earlier and allows for pivoting or terminating experiments in a timely manner.

High-quality real-time data is needed as input for closed-loop control so that critical process parameters and critical product attributes remain within target levels throughout culture. For example, different cell types require different levels of dissolved oxygen for optimal cell health and phenotypic expression. Real-time dissolved oxygen data can be used to control levels within a pre-defined range through methods such as media oxygenation, perfusion, stirring, or shaking.

KR: How can these sensor-based technologies better inform biopharmaceutical applications?

JM: We’re on a mission to take the guesswork out of bioprocessing and illuminate the black boxes of mammalian and microbial cell culture. These sensor-based technologies enable digitally simplified bioprocessing: real-time actionable insights through miniaturized smart sensors, AI and machine learning, from the lab to the production floor. We are expanding our sensing platform to include sensors for additional analytes such as glucose and are developing closed-loop control systems for automated feeding and gas control. As biologic drugs, cell and gene therapy products and personalized medicine come to the forefront of medicine, process control, reproducibility, cost reduction, time to market and high-quality products gain paramount importance as truly enabling technologies. SBI is poised to become a leading provider of these enabling technologies to our biopharma partners.

John Moore was speaking to Kate Robinson, Editorial Assistant for Technology Networks.