NONINVASIVE PROCESS MONITORING FOR CELL THERAPY APPLICATIONS

Abstract

Cell therapies are therapies where cellular materials are injected, grafted, or implanted into the patient body to produce medicinal effects. As a growing field, cell therapy has demonstrated significant potential in the treatment of diseases ranging from diabetes and soft tissue wounds to cancer, nervous system, and genetic disorders. Despite the promising results from cell therapies, the manufacturing process of these therapies is associated with issues such as a lack of appropriate small-scale models and poorly defined manufacturing processes which contribute to the high cost of these therapies. Cell culture is the longest step in the manufacturing process of cell therapies, and the characteristics of cells could be affected by critical parameters in the cell culture environment, such as pH, dissolved carbon dioxide (DCO2), and dissolved oxygen (DO). Therefore, cell culture is one of the mostcritical steps in the manufacturing process of cell therapies because it defines the quality and efficacy of cell therapies. The integration of sensors with the manufacturing process helps in optimizing critical environmental parameters and mitigating problems at the early stages of the process. Therefore, bioreactors, as valuable platforms for cell culture processes, must be equipped with sensors to measure the critical process parameters and develop appropriate control methods. 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 the final products in these processes are cells. Unlike other biologics, cells cannot be sterilized due to being fragile. Therefore, developing a noninvasive monitoring technique is beneficial because it helps eliminate the chance of contamination during the monitoring process. This dissertation is an effort to develop a technology capable of simultaneous monitoring of pH, DCO2, and DO without requiring direct contact with the cell culture environment. Sensors for monitoring pH, DCO2, and DO analytes were previously developed at CAST. The techniques were further developed to achieve noninvasive methods for monitoring pH, DCO2, and DO. The principles utilized in noninvasive techniques, the experimental studies, and the results are discussed in this report. Subsequently, the flow cell, the technology designed for simultaneous monitoring of pH, DCO2, and DO outside the bioreactor, is introduced. The flow cell was developed by combining the principles utilized in individual noninvasive techniques for monitoring pH, DCO2, and DO. The proposed flow cell prototype was investigated in multiple experiments, and the results from studies indicate the efficacy of flow cell in tracking changes inside the bioreactor.