A Fully-Closed and Automated Hollow Fiber Bioreactor for Clinical-Grade Manufacturing of Human Mesenchymal Stem/Stromal Cells

Mizukami, Amanda; Abreu-Neto, Mário Soares; Moreira, Francisco; Fernandes‐Platzgummer, Ana; Huang, Yao‐Zeng; Milligan, William; Cabral, Joaquim M. S.; Silva, Cláudia L. da; Covas, Dimas Tadeu; Swiech, Kamilla

doi:10.1007/s12015-017-9787-4

Cited by 30 publications

(17 citation statements)

References 6 publications

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“…A maximum 40-fold expansion factor (1.6·10 8 cells in total at the 250 cm 3 scale) was reported, leading to final cell densities of 6·10 4 cells cm −2 (GFP-MSCs) or 1.5·10 4 cells cm −2 (placenta MSCs). A hollow-fiber reactor resulted in an expansion factor of 6 (2.4·10 4 cells cm −2 , 3·10 8 cells total) [ 85 ], with production rates of 5·10 7 cells d −1 (for further reading, see [ 86 – 88 ]), whereas a 257 cm 3 fibrous-bed reactor achieved a 9-fold expansion factor (3·10 3 cells cm −2 , 9.2·10 7 cells total) [ 89 ]. Therefore, although hMSCs can be expanded in FBRs, the harvest problem remains to be addressed.…”

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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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%

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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show abstract

“…While this analysis was performed with BM-MSCs, which involve a particularly tedious and expensive collection method, other types of MSCs with less invasive collection methods, such as adipose stem cells or umbilical cord matrix/Wharton's Jelly MSCs (UCM-MSCs/WJ-MSCs), have been isolated and expanded with hPL with improvement in the proliferative potential with lower cell size while retaining potency attributes [37,38,[65][66][67]. As a xeno-free alternative, hPL has the caveats of being dependent on donor samples, high batch to batch variability, poor definition of its components and the possible transmission of viruses.…”

Section: Considerations For Model-driven Cost-effective Process Transfermentioning

confidence: 99%

Modeling Biological and Economic Uncertainty on Cell Therapy Manufacturing: the Choice of Culture Media Supplementation

2018

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To evaluate the cost-effectiveness of autologous cell therapy manufacturing in xeno-free conditions. Materials & methods: Published data on the isolation and expansion of mesenchymal stem/stromal cells introduced donor, multipassage and culture media variability on cell yields and process times on adherent culture flasks to drive cost simulation of a scale-out campaign of 1000 doses of 75 million cells each in a 400 square meter Good Manufacturing Practices facility. Results & conclusion: Passage numbers in the expansion step are strongly associated with isolation cell yield and drive cost increases per donor of $1970 and 2802 for fetal bovine serum and human platelet lysate. Human platelet lysate decreases passage numbers and process costs in 94.5 and 97% of donors through lower facility and labor costs. Cost savings are maintained with full equipment depreciation and higher numbers of cells per dose, highlighting the number of cells per passage step as the key cost driver.

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“…In the same year, it was also reported that HPL supplemented medium could be used to isolate UCB MSCs and subsequently expand them using spinner flasks . Since the publication of these pioneering works, multiple studies have been carried out to expand MSCs from various sources using HPL supplementation in different bioreactor systems like stirred reactors of different volumes (100 ml to 50 l) and hollow fiber systems .…”

Section: Introductionmentioning

confidence: 99%

Human Platelet Lysate Improves Bone Forming Potential of Human Progenitor Cells Expanded in Microcarrier-Based Dynamic Culture

Gupta

Hall

Geris

et al. 2019

Stem Cells Translational Medicine

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Xenogeneic‐free media are required for translating advanced therapeutic medicinal products to the clinics. In addition, process efficiency is crucial for ensuring cost efficiency, especially when considering large‐scale production of mesenchymal stem cells (MSCs). Human platelet lysate (HPL) has been increasingly adopted as an alternative for fetal bovine serum (FBS) for MSCs. However, its therapeutic and regenerative potential in vivo is largely unexplored. Herein, we compare the effects of FBS and HPL supplementation for a scalable, microcarrier‐based dynamic expansion of human periosteum‐derived cells (hPDCs) while assessing their bone forming capacity by subcutaneous implantation in small animal model. We observed that HPL resulted in faster cell proliferation with a total fold increase of 5.2 ± 0.61 in comparison to 2.7 ± 02.22‐fold in FBS. Cell viability and trilineage differentiation capability were maintained by HPL, although a suppression of adipogenic differentiation potential was observed. Differences in mRNA expression profiles were also observed between the two on several markers. When implanted, we observed a significant difference between the bone forming capacity of cells expanded in FBS and HPL, with HPL supplementation resulting in almost three times more mineralized tissue within calcium phosphate scaffolds. FBS‐expanded cells resulted in a fibrous tissue structure, whereas HPL resulted in mineralized tissue formation, which can be classified as newly formed bone, verified by μCT and histological analysis. We also observed the presence of blood vessels in our explants. In conclusion, we suggest that replacing FBS with HPL in bioreactor‐based expansion of hPDCs is an optimal solution that increases expansion efficiency along with promoting bone forming capacity of these cells. Stem Cells Translational Medicine 2019;8:810&821

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A Fully-Closed and Automated Hollow Fiber Bioreactor for Clinical-Grade Manufacturing of Human Mesenchymal Stem/Stromal Cells

Cited by 30 publications

References 6 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

Modeling Biological and Economic Uncertainty on Cell Therapy Manufacturing: the Choice of Culture Media Supplementation

Human Platelet Lysate Improves Bone Forming Potential of Human Progenitor Cells Expanded in Microcarrier-Based Dynamic Culture

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