Large-Scale Automated Hollow-Fiber Bioreactor Expansion of Umbilical Cord-Derived Human Mesenchymal Stromal Cells for Neurological Disorders

Vymětalová, Ladislava; Kučírková, Tereza; Knopfová, Lucia; Pospíšilová, Veronika; Kasko, Tomas; Lejdarová, Hana; Makaturova, Eva; Kuglík, Petr; Oralová, Veronika; Matalová, Eva; Beneš, Petr; Kořístek, Zdeněk; Forostyak, Serhiy

doi:10.1007/s11064-019-02925-y

Cited by 28 publications

(19 citation statements)

References 42 publications

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“…Many types of bioreactors, including hollow fiber bioreactor (Quantum Cell Expansion System) [ 19 , 38 ], stirred tank bioreactor (UniVessel® SU bioreactor [ 28 ], Mobius® bioreactor [ 21 ], Celligen 310 bioreactor [ 26 , 31 , 35 ], Vertical Wheel bioreactor [ 27 ], Biostat Qplus bioreactor [ 27 ], and BioFlo 110 bioreactor [ 32 ]), and multiplate bioreactor (Pall Life Sciences Xpansion Multiplate Bioreactor) [ 39 ], have been tested for large-scale expansion of MSCs. Most studies used commercially available bioreactors with capacity ranging from 1.3 l to 50 l except Egger et al who built their own stirred tank bioreactor for the expansion of AT-MSCs [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

Large-Scale Expansion of Human Mesenchymal Stem Cells

Hassan

Yazid

Yunus

et al. 2020

Stem Cells International

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Mesenchymal stem cells (MSCs) are multipotent stem cells with strong immunosuppressive property that renders them an attractive source of cells for cell therapy. MSCs have been studied in multiple clinical trials to treat liver diseases, peripheral nerve damage, graft-versus-host disease, autoimmune diseases, diabetes mellitus, and cardiovascular damage. Millions to hundred millions of MSCs are required per patient depending on the disease, route of administration, frequency of administration, and patient body weight. Multiple large-scale cell expansion strategies have been described in the literature to fetch the cell quantity required for the therapy. In this review, bioprocessing strategies for large-scale expansion of MSCs were systematically reviewed and discussed. The literature search in Medline and Scopus databases identified 26 articles that met the inclusion criteria and were included in this review. These articles described the large-scale expansion of 7 different sources of MSCs using 4 different bioprocessing strategies, i.e., bioreactor, spinner flask, roller bottle, and multilayered flask. The bioreactor, spinner flask, and multilayered flask were more commonly used to upscale the MSCs compared to the roller bottle. Generally, a higher expansion ratio was achieved with the bioreactor and multilayered flask. Importantly, regardless of the bioprocessing strategies, the expanded MSCs were able to maintain its phenotype and potency. In summary, the bioreactor, spinner flask, roller bottle, and multilayered flask can be used for large-scale expansion of MSCs without compromising the cell quality.

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Section: Resultsmentioning

confidence: 99%

Large-Scale Expansion of Human Mesenchymal Stem Cells

Hassan

Yazid

Yunus

et al. 2020

Stem Cells International

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“…To scale up EV production for industrialization, 3D-culture in bioreactors has been tested, such as multilayered cell culture flasks, hollow fiber bioreactors, stirred-tank bioreactors, and spheroidal aggregates of MSCs. Hollow fiber and stirred-tank bioreactors are the more promising approaches because they are closed and GMP-compatible scalable systems that provide a high surface-to-volume ratio for MSC growth ( Mendt et al, 2018 ; Mennan et al, 2019 ; Vymetalova et al, 2020 ). EV production in bioreactors is increased at least by 40-fold compared with 2D culture systems ( Watson et al, 2016 ).…”

Section: Challenges For the Industrial Production Of Gmp-grade Extracmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Opportunities and Challenges for Clinical Translation

Maumus

Rozier

Boulestreau

et al. 2020

Front. Bioeng. Biotechnol.

105

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Extracellular vesicles (EVs), including exosomes and microvesicles, derived from mesenchymal stem/stromal cells (MSCs) exert similar effects as their parental cells, and are of interest for various therapeutic applications. EVs can act through uptake by the target cells followed by release of their cargo inside the cytoplasm, or through interaction of membrane-bound ligands with receptors expressed on target cells to stimulate downstream intracellular pathways. EV-based therapeutics may be directly used as substitutes of intact cells or after modification for targeted drug delivery. However, for the development of EV-based therapeutics, several production, isolation, and characterization requirements have to be met and the quality of the final product has to be tested before its clinical implementation. In this review, we discuss the challenges associated with the development of EV-based therapeutics and the regulatory specifications for their successful clinical translation.

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“…It is not a scalable system as it requires a larger footprint for handling due to its restrictive surface-to-volume ratio, its nonhomogenous expansion due to non-uniform surface coating resulting in batch-to-batch variability, it being laborious, and the fact that media exchange and cell harvesting can be impacted by the handling of multiple stackers at the same time (Cherian et al, 2020). Alternatively, GMP-compliant, closed automated and single-use systems may be suitable for hMSC manufacturing including hollow fiber-based (HF) continuous perfusion device, the Quantum cell expansion system from Terumo BCT (Hanley et al, 2014;Barckhausen et al, 2016;Khan et al, 2017;Frank et al, 2019;Vymetalova et al, 2020), 2D multiplate-based (MP) Xpansion R bioreactor system from Pall corporation (Rouard et al, 2020), and packed-bed (PB) iCeLLis R bioreactor from Pall corporation (Mizukami et al, 2018) (Figure 2B). Nonetheless, all of these systems (HF, MP, and PB) are better suited for autologous therapy or scale-out allogeneic therapy as they are limited by scalability, poor harvesting efficiency (especially PB), and the least cost-effective technology (Mizukami et al, 2018).…”

Section: Cell Expansion Processing and Formulationmentioning

confidence: 99%

Acceleration of Translational Mesenchymal Stromal Cell Therapy Through Consistent Quality GMP Manufacturing

Jayaraman¹,

Lim²,

Ng³

et al. 2021

Front. Cell Dev. Biol.

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Human mesenchymal stromal cell (hMSC) therapy has been gaining immense interest in regenerative medicine and quite recently for its immunomodulatory properties in COVID-19 treatment. Currently, the use of hMSCs for various diseases is being investigated in >900 clinical trials. Despite the huge effort, setting up consistent and robust scalable manufacturing to meet regulatory compliance across various global regions remains a nagging challenge. This is in part due to a lack of definitive consensus for quality control checkpoint assays starting from cell isolation to expansion and final release criterion of clinical grade hMSCs. In this review, we highlight the bottlenecks associated with hMSC-based therapies and propose solutions for consistent GMP manufacturing of hMSCs starting from raw materials selection, closed and modular systems of manufacturing, characterization, functional testing, quality control, and safety testing for release criteria. We also discuss the standard regulatory compliances adopted by current clinical trials to broaden our view on the expectations across different jurisdictions worldwide.

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Large-Scale Automated Hollow-Fiber Bioreactor Expansion of Umbilical Cord-Derived Human Mesenchymal Stromal Cells for Neurological Disorders

Cited by 28 publications

References 42 publications

Large-Scale Expansion of Human Mesenchymal Stem Cells

Large-Scale Expansion of Human Mesenchymal Stem Cells

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Opportunities and Challenges for Clinical Translation

Acceleration of Translational Mesenchymal Stromal Cell Therapy Through Consistent Quality GMP Manufacturing

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