Cifuentes-Maury, Said J.

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    Development of a culture substrate for the scale-up expansion of human Mesenchymal stromal cells for therapeutic applications
    (2023-03-21) Cifuentes-Maury, Said J.; Domenech-García, Maribella; College of Engineering; Almodovar-Montañez, Jorge; Torres-Lugo, Madeline; Acevedo-Rullán, Aldo; Other; Vásquez-Urbano, Pedro
    The cell manufacturing field is constantly growing, each time promoting new and better cell fabrication strategies to allow the arrival of the widely expected Mesenchymal stromal cells’ (MSCs) based cell therapies to reach the US market. This work has devoted a significant effort to generating and characterizing new cell culture strategies using the layer-by-layer (LbL) technique to produce polymeric coatings for the expansion of MSCs. It has also studied the effects of used materials on cell responses at the adhesion level, growth, proliferation, survival, senescence, immunomodulation, and surface remodeling. As an initial measure, we generated layers composed of Heparin and Collagen (HEP/COL) and showed that they were physically and chemically stable for up to 30 days at room temperature. In addition, there was proven that multilayers promoted substantial improvements in cell expansion and secretion of soluble factors, even under reduced serum conditions. Afterward, evaluations were carried out at the molecular level exploring the role of integrin-matrix interactions in the LbL-deposited coatings, confirming an effect on cell adhesion through α2β1 integrins, which is linked to cell survival via the FAK/ERK activation cascade. Finally, multilayers were created using COL and various recombinant forms of Heparan Sulfate (rHS/COL), identifying significant differences in protein release profiles in response to inherent sulfation degrees, as well as improvements in cell proliferation, evaluated both in planar and microcarriers culture systems under serum-free conditions. This dissertation demonstrates that the polymeric formations of HEP/COL and rHSs/COL generated by the LbL method have great potential for MSC expansion, generating new opportunities for the cell manufacturing field.