The Challenge of Human Mesenchymal Stromal Cell Expansion: Current and Prospective Answers

Elseberg, Christiane; Leber, Jasmin; Weidner, Tobias; PeterCzermak,

doi:10.5772/66901

Cited by 5 publications

(3 citation statements)

References 130 publications

(206 reference statements)

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“…The main conditions required to grow MSCs in bioreactors include a large surface area to volume ratio, a closed system, automated inoculation and harvesting, and the automated online control of culture parameters. Several controlled bioreactor types are suitable for the cultivation of hMSCs, including classical fixed bed, fluidized bed and stirred tank reactors, and alternative systems such as wave reactors, wall-rotating systems, and Vertical-Wheel™ reactors [ 72 ]. Moreover, hMSC expansion can also be achieved in spinner flasks.…”

Section: Bioreactor Technologies For the 3d Cultivation Of Mscsmentioning

confidence: 99%

“…The cultivation of hMSCs in STRs usually involves microcarriers, but the growth of hMSCs as aggregates or spheroids has also been described. The maximum scale of hMSC expansion reported thus far was achieved in a 50 L STR with a 35 L working volume, resulting in a 50-fold expansion and 2.6·10 10 cells in total [ 72 ]. The expansion of hMSCs is usually a batch-mode process, whereas fed-batch processes are often more advantageous because the process starts with a small inoculum in a low working volume, which increases over time with the simultaneous addition of carrier (for carrier-based processes) leading to higher expansion factors [ 73 ].…”

Section: Bioreactor Technologies For the 3d Cultivation Of Mscsmentioning

confidence: 99%

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Three-Dimensional Bioreactor Technologies for the Cocultivation of Human Mesenchymal Stem/Stromal Cells and Beta Cells

Petry

Weidner

Czermak

et al. 2018

Stem Cells International

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Diabetes is a prominent health problem caused by the failure of pancreatic beta cells. One therapeutic approach is the transplantation of functional beta cells, but it is difficult to generate sufficient beta cells in vitro and to ensure these cells remain viable at the transplantation site. Beta cells suffer from hypoxia, undergo apoptosis, or are attacked by the host immune system. Human mesenchymal stem/stromal cells (hMSCs) can improve the functionality and survival of beta cells in vivo and in vitro due to direct cell contact or the secretion of trophic factors. Current cocultivation concepts with beta cells are simple and cannot exploit the favorable properties of hMSCs. Beta cells need a three-dimensional (3D) environment to function correctly, and the cocultivation setup is therefore more complex. This review discusses 3D cultivation forms (aggregates, capsules, and carriers) for hMSCs and beta cells and strategies for large-scale cultivation. We have determined process parameters that must be balanced and considered for the cocultivation of hMSCs and beta cells, and we present several bioreactor setups that are suitable for such an innovative cocultivation approach. Bioprocess engineering of the cocultivation processes is necessary to achieve successful beta cell therapy.

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Section: Bioreactor Technologies For the 3d Cultivation Of Mscsmentioning

confidence: 99%

Section: Bioreactor Technologies For the 3d Cultivation Of Mscsmentioning

confidence: 99%

Three-Dimensional Bioreactor Technologies for the Cocultivation of Human Mesenchymal Stem/Stromal Cells and Beta Cells

Petry

Weidner

Czermak

et al. 2018

Stem Cells International

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“…This enables the production of MSCs with consistent identity and potency (CQAs). Many different bioreactor types have been used for the in vitro expansion of MSCs, including fixed bed, fluidized bed, and stirred tank reactors, as well as newer innovations such as wave reactors, wall-rotating systems, and vertical wheel reactors [76]. However, most studies have involved only two types of reactor: stirred tank or fixed bed, and these are discussed in more detail below.…”

Section: The Expansion Of Mscs In Bioreactorsmentioning

confidence: 99%

Bioprocess Development for Human Mesenchymal Stem Cell Therapy Products

Barekzai¹,

Petry²,

Zitzmann³

et al. 2020

New Advances on Fermentation Processes

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Mesenchymal stem cells (MSCs) are advanced therapy medicinal products used in cell therapy applications. Several MSC products have already advanced to phase III clinical testing and market approval. The manufacturing of MSCs must comply with good manufacturing practice (GMP) from phase I in Europe and phase II in the US, but there are several unique challenges when cells are the therapeutic product. Any GMP-compliant process for the production of MSCs must include the expansion of cells in vitro to achieve a sufficient therapeutic quantity while maintaining high cell quality and potency. The process must also allow the efficient harvest of anchorage-dependent cells and account for the influence of shear stress and other factors, especially during scale-up. Bioreactors are necessary to produce clinical batches of MSCs, and bioprocess development must therefore consider this specialized environment. For the last 10 years, we have investigated bioprocess development as a means to produce high-quality MSCs. More recently, we have also used bioreactors for the cocultivation of stem cells with other adult cells and for the production of MSC-derived extracellular vesicles. This review discusses the state of the art in bioprocess development for the GMP-compliant manufacture of human MSCs as products for stem cell therapy.

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Implementation of mDoE‐methods to a microcarrier‐based expansion processes for mesenchymal stem cells

Kuchemüller,

Pörtner,

Möller

2024

Biotechnology Progress

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The need for advanced therapy medicinal products (ATMPs) has gained increased attention in recent years. In this respect, a well‐designed cell expansion process is needed to efficiently manufacture the required number of cells with the desired product quality. This step is challenging due to the biological complexity of the respective primary cell (e.g., mesenchymal stem cells (MSC)) and the usage of microcarrier‐based expansion systems. One accelerating approach for process design is model‐assisted Design of Experiments (mDoE) combining mathematical process models and statistical tools. In this study, the mDoE workflow was used for the development of an expansion processes with human immortalized mesenchymal stem cells (hMSC‐TERT) and the aim of maximizing cell yield assuming only a limited amount of prior knowledge at a very early stage of development. First, suitable microcarriers for expansion in shake flasks were screened and the differentiation of the cells was proven. Second, initial experiments were performed to generate prior knowledge, which was then used to set up the mathematical model and to estimate the model parameters. Finally, the mDoE was used to determine and evaluate the design space to be performed experimentally. Overall, a cell expansion process using microcarriers in a shake flask culture was successfully implemented and a significant increase in cell yield (up to 6,2‐fold) was achieved compared to literature.

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The Challenge of Human Mesenchymal Stromal Cell Expansion: Current and Prospective Answers

Cited by 5 publications

References 130 publications

Three-Dimensional Bioreactor Technologies for the Cocultivation of Human Mesenchymal Stem/Stromal Cells and Beta Cells

Three-Dimensional Bioreactor Technologies for the Cocultivation of Human Mesenchymal Stem/Stromal Cells and Beta Cells

Bioprocess Development for Human Mesenchymal Stem Cell Therapy Products

Implementation of mDoE‐methods to a microcarrier‐based expansion processes for mesenchymal stem cells

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