Vida Rahmatnejad - PhD Dissertation Defense

NONINVASIVE PROCESS MONITORING FOR CELL THERAPY APPLICATIONS

Cell therapies are therapies where cellular materials are utilized for producing medicinal effects. As a growing field, cell therapy has shown promising results in treating diseases ranging from diabetes and soft tissue wounds to the nervous system, genetic disorders, and cancer. Cell culture is the longest step in the manufacturing process of cell therapies, and cell characteristics could be affected by this process. Therefore, cell culture is one of the most critical manufacturing steps because it defines the quality and efficacy of cell therapies. Bioreactors are valuable platforms that help achieve optimal conditions during cell culture and are considered essential tools for achieving consistent and cost-effective cell therapy production processes. On the other hand, to achieve optimal performance and consistency, it is critical to equip bioreactors with monitoring systems and study the environmental parameters such as pH, dissolved carbon dioxide (DCO₂), and dissolved oxygen (DO). The integration of sensors with the manufacturing process helps in optimizing environmental parameters and mitigating problems at the early stages of the process. 

Despite the advantages that monitoring systems provide, their presence in the cell culture environment increases the risk of contamination. Avoiding contamination in the manufacturing process of cell therapies is of high importance. Because cells are the final products in these processes and cannot be sterilized at the final stage due to being fragile. Therefore, developing a method for noninvasive monitoring of the cell culture process helps eliminate the chance of contamination. This work is an effort to create a technology capable of monitoring pH, DCO₂, and DO without requiring direct contact with the cell culture environment. Sensors for monitoring individual pH, DCO₂, and DO analytes were previously developed at CAST. In this report, the noninvasive techniques developed for monitoring individual analytes are discussed initially. Subsequently, the flow cell, the technology designed for simultaneous monitoring of pH, DCO₂, and DO outside the bioreactor, is introduced. The flow cell is developed based on the principles utilized in techniques for the noninvasive measurement of individual analytes. The proposed prototypes for noninvasive measurements of pH, DCO₂, and DO, as well as flow cell are investigated in multiple experiments. The experiments include creating different pH, DCO₂ and DO levels through sparging gases and cell culture processes. The results from validation studies are promising and indicate the efficacy of the noninvasive methods. Furthermore, the results from flow cell studies suggest that the flow cell effectively tracks changes inside the bioreactor, and measurements from this technique are comparable with the measures from control methods obtained from inside the bioreactor.

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