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Biochemical Engineering Journal
Vol. 120, 2017, Pages: 49–62

Process development for expansion of human mesenchymal stromal cells in a 50 L single-use stirred tank bioreactor

Tristan Lawson, Daniel E. Kehoe1, Aletta C. Schnitzler, Peter J. Rapiejko, Kara A. Der, Kathryn Philbrick, Sandhya Punreddy, Susan Rigby, Robert Smith, Qiang Feng, Julie R. Murrell, Martha S. Rook

EMD Millipore Corporation, 80 Ashby Road, Bedford, MA 01730, United States.


The application of cell-based therapeutics requires development of refined and scalable culture processes. Stirred tank bioreactors facilitate growth of human mesenchymal stromal cells (hMSC) while meeting these needs. A process for expansion of hMSCs in a 50 L bioreactor was developed. Parameters evaluated include agitation rate, pH and dissolved oxygen (DO) control set-points, and media formulation. The pH and DO levels were determined empirically in 3 L bioreactors prior to implementation at the 50 L scale. The agitation operating range for microcarrier cultures in the 50 L bioreactor was calculated based on theoretical and empirical analyses of solid suspension and shear limitations. Additionally, small-scale experiments demonstrated that hMSC growth was improved in αMEM supplemented with human platelet lysate in comparison to DMEM supplemented with FBS. A 43-fold expansion of harvested hMSCs was achieved in 11 days in a 50 L bioreactor incorporating these process improvements. Cells expanded in the bioreactor exhibited the expected surface marker expression, trilineage differentiation potential, T cell growth inhibition and indoleamine 2,3-dioxygenase inducibility. The results highlight that identification of optimal pH, DO, agitation rates and culture medium for microcarrier-based bioreactor expansion of adherent cells is paramount to developing a platform to support cell-based therapies.

Keywords: Bioreactors; Mesenchymal stem cells; Microcarriers; Scale-up; Bioprocess design; Large scale cultivation.

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