Machine learning-based model predictive controller design for cell culture processes.

The biopharmaceutical industry continuously seeks to optimize the critical quality attributes to maintain the reliability and cost-effectiveness of its products. Such optimization demands a scalable and optimal control strategy to meet the process constraints and objectives. This work uses a model predictive controller (MPC) to compute an optimal feeding strategy leading to maximized cell growth and metabolite production in fed-batch cell culture processes. The lack of high-fidelity physics-based models and the high complexity of cell culture processes motivated us to use machine learning algorithms in the forecast model to aid our development. We took advantage of linear regression, the Gaussian process and neural network models in the MPC design to maximize the daily protein production for each batch. The control scheme of the cell culture process solves an optimization problem while maintaining all metabolites and cell culture process variables within the specification. The linear and nonlinear models are developed based on real cell culture process data, and the performance of the designed controllers is evaluated by running several real-time experiments.

Effects of hyperthermia on the differentiation and growth of K562 erythroleukemic cell line.

Several agents are known to induce differentiation in the human erythroleukemic cell line K562. In this work we have studied the ability of hyperthermia to induce differentiation in the K562 cell line. K562 cells were treated with hyperthermia in the range of 41-45 degrees C. Cell proliferation and the plating efficiency of heat treated cells along with their hemoglobin synthesis was measured and compared with controls. Hyperthermia severely inhibited the growth of K562 cells in the suspension culture in a time- and temperature-dependent manner. Sixty minutes of heating and 44 and 40 min of heating at 45 degrees C totally inhibited the growth of the cells. The number of clonogenic cells also decreased as a result of heat treatment. Extended periods of heating for more than 2 h at 41 degrees C resulted in thermal adaptation. Hyperthermia-induced hemoglobin synthesis by these cells, only at 42 and 43 degrees C. Maximum induction was observed after heat treatment for 80 min at 43 degrees C and 180 min at 42 degrees C. At lower temperature, although the fraction of surviving cells was high, but no signs of hemoglobin synthesis could be observed. At temperatures higher than 43 degrees C, the fraction of surviving cells decreased rapidly and also no signs of hemoglobin synthesis could be detected. At the two selective temperatures, hemoglobin synthesis started 4 days after heat treatment. The results showed that hyperthermia caused cytotoxicity and growth arrest and induced differentiation as judged by hemoglobin synthesis and reduced clonogenicity in this cell line. This is the first time that a physical agent has been shown to induce differentiation in erythroleukemic cell lines.