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Development of an optimized perfused-continuous process of culture of human umbilical cord mesenchymal stem cells (hMSC) grown on innovative adhesion supports

Abstract : Mesenchymal stem cells (MSCs) show great interest in cellular therapies. Their various characteristics such as their immuno-modulatory properties, their ability to differentiate, and also the secretion of factors, are numerous and promising for new clinical treatments for diseases where few therapies are proposed or have few efficiencies. The doses to be injected for significant results must be repeated and generally contain high quantities of cells (106 cells kg-1 per patient approx). Large scale production methods must be implemented to meet the demand, and in the least costly way possible. In this PhD work, the main objective was to develop a scalable process adapted to these support-dependent cells. For this end, a first study allowed to understand part of the mechanisms of interaction of cells with their growth supports, the microcarriers. The adhesion time but also the cell migrations between microcarriers were characterized and evaluated. A strategy of fed-batch mode strategy with microcarriers addition at specific times in the culture was also proposed. Following this, the second part of the study of this work was to determine the efficiency on larger scale expansion process (1.5 L), using of innovative microcarriers developed by the partner teams of the ‘ImprovesStem’ European project. Several microcarriers candidates with chemically modified surface proved to be promising for the expansion of Wharton’s jelly stem cells. Finally, in the last part of the thesis, an innovative process based on the removal of empty microcarriers, avoiding the risk of deleterious frictions between highly concentrated microcarriers was proposed. Moreover, an on-line monitoring of viable cell concentration was carried-out in the stirred tank bioreactor. Innovative commercial microcarriers, soluble under the action of enzymes, were used in this last part of the study. An improvement of the expansion factor (by a factor of 1.5) was obtained in this continuous-perfused mode of culture in the stirred bioreactor. In addition, these enzymatically-soluble commercial microcarriers allowed for an excellent detachment yield, essential to consider their use in cell therapy.
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Theses
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http://docnum.univ-lorraine.fr/ulprive/DDOC_T_2020_0113_SION.pdf
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https://hal.univ-lorraine.fr/tel-03001312
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Submitted on : Thursday, November 12, 2020 - 12:23:08 PM
Last modification on : Friday, November 13, 2020 - 3:26:07 AM

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  • HAL Id : tel-03001312, version 1

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Caroline Sion. Development of an optimized perfused-continuous process of culture of human umbilical cord mesenchymal stem cells (hMSC) grown on innovative adhesion supports. Biotechnology. Université de Lorraine, 2020. English. ⟨NNT : 2020LORR0113⟩. ⟨tel-03001312⟩

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