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Real-time monitoring and control of CHO cell apoptosis by in situ multifrequency scanning dielectric spectroscopy

Ma, Fuduo, Zhang, An, Chang, David, Velev, Orlin D., Wiltberger, Kelly, Kshirsagar, Rashmi
Process biochemistry 2019 v.80 pp. 138-145
apoptosis, bioreactors, cell culture, cell physiology, chemical treatment, dielectric spectroscopy, glucose, mammals, manufacturing, monitoring, physiological state, process control, viability
Process control strategies based on the physiological status of cells have recently been used to enhance mammalian cell culture productivity and robustness. In this study, we investigated the feasibility of using full-spectrum dielectric spectroscopy for detecting shifts in cell physiology and as a feedback tool to increase process efficiency. Multi-frequency permittivity spectra were collected from cell culture processes in which apoptosis was induced by glucose depletion, nutrient depletion, or chemical treatment. Meanwhile, key parameters of critical frequency (fc) and Cole-Cole alpha (α) were calculated in real time from the β-dispersion curve and correlated to data from off-line viability measurements. Results show that physiological changes in apoptotic cells were reflected in the on-line parameters earlier than from off-line methods. Using information from the on-line parameters, we achieved partial or full recovery from early apoptosis by replenishing the depleted feed. We also demonstrate that by using trends in fc, we could detect a deviation in media preparation in a manufacturing process which could not be achieved using conventional measurements. The results demonstrate that full-spectrum dielectric spectroscopy can be used as a facile tool for early detection of physiological changes and process adjustment in real-time to enhance bioreactor process productivity and robustness.