A team of Merck scientists is shining a new spotlight on an old bioprocessing workhorse—permittivity, which is how much electrical energy a culture can store and correlates with the amount of living cells. As these scientists argue, though, permittivity can do far more than track viable-cell density. In a study led by Shahid Rameez, PhD, director of bioprocess drug substance development and commercialization at Merck, researchers showed that dielectric spectroscopy, interpreted through Cole–Cole model parameters, can function as an in-line early-warning system for apoptosis and other stress responses in cultures of Chinese hamster ovary (CHO) cells.
The problem is familiar across biologics manufacturing: many of the most informative cell-health readouts are still offline. Trypan-blue viability, staining assays, metabolite panels, and other spot checks can tell a detailed story, but usually after the plot has already shifted. When a culture starts sliding toward apoptosis, whether from nutrient limitation, conductivity shifts, or shear stress, teams often discover it only once viability or productivity has measurably declined.
Rameez and colleagues focused on two Cole–Cole parameters derived from multi-frequency permittivity scans: critical frequency (fc) and delta epsilon (Δε). Rather than treating permittivity as a single number, the approach uses the shape of the beta-dispersion curve to infer changing cellular properties. In practical terms, the team positions fc and Δε as key performance indicators that move in recognizable patterns as cells transition from healthy growth into stress and apoptotic progression.
Batch cultures
In batch cultures, the researchers intentionally drove nutrient depletion to force stress responses. They observed that fc rose from baseline while Δε declined, tracking with hallmarks of apoptosis such as shrinking cell size—often before traditional viability readouts clearly signaled trouble. To probe what those electrical signals meant biologically, the team paired the online readouts with proteomics. The result: upregulation of proteins linked to cellular stress pathways supported the idea that shifts in fc and Δε reflect real physiological strain rather than sensor noise.
The work becomes particularly relevant in perfusion, where high cell densities and continuous media exchange can mask emerging limitations. The study reports that fc drifted upward in perfusion runs when effective nutrient availability tightened, and that abrupt deviations—like excessive recirculation flow leading to shear—produced pronounced fc increases alongside Δε decreases. Importantly, the team tested a control strategy: when fc deviated beyond a defined threshold, they increased perfusion rates to restore fc toward baseline. That adjustment improved culture health and supported higher output compared with the control condition.
The researchers frame dielectric spectroscopy as a simpler, more readily deployable complement to information-rich but model-heavy tools such as Raman. If adopted broadly, fc and Δε could help manufacturers move from reactive troubleshooting to proactive intervention—catching apoptosis earlier, tuning feeding and perfusion faster, and potentially rescuing runs before quality and yield are compromised.