Dispersible and Dissolvable Porous Microcarrier Tablets Enable Efficient Large-Scale Human Mesenchymal Stem Cell Expansion

Yan, Xiaoliang; Zhang, Kun; Yang, Yanping; Deng, Dongkai; Lyu, Cheng; Xu, Huanye; Liu, Wei; Du, Yanan

doi:10.1089/ten.tec.2020.0039

Cited by 50 publications

(56 citation statements)

References 43 publications

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“…For example, when using the microcarriers with a thermo-sensitive surface, the temperature should be well-controlled throughout bioprocessing. To simplify the harvesting process, novel dispersible and dissolvable porous microcarriers have also been reported recently (Yan et al, 2020 ).…”

Section: Bioprocessing For Hmsc Productionmentioning

confidence: 99%

Influence of Microenvironment on Mesenchymal Stem Cell Therapeutic Potency: From Planar Culture to Microcarriers

Tsai

Jeske

Chen

et al. 2020

Front. Bioeng. Biotechnol.

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Human mesenchymal stem cells (hMSCs) are a promising candidate in cell therapy as they exhibit multilineage differentiation, homing to the site of injury, and secretion of trophic factors that facilitate tissue healing and/or modulate immune response. As a result, hMSC-derived products have attracted growing interests in preclinical and clinical studies. The development of hMSC culture platforms for large-scale biomanufacturing is necessary to meet the requirements for late-phase clinical trials and future commercialization. Microcarriers in stirred-tank bioreactors have been widely utilized in large-scale expansion of hMSCs for translational applications because of a high surface-to-volume ratio compared to conventional 2D planar culture. However, recent studies have demonstrated that microcarrier-expanded hMSCs differ from dish-or flask-expanded cells in size, morphology, proliferation, viability, surface markers, gene expression, differentiation potential, and secretome profile which may lead to altered therapeutic potency. Therefore, understanding the bioprocessing parameters that influence hMSC therapeutic efficacy is essential for the optimization of microcarrier-based bioreactor system to maximize hMSC quantity without sacrificing quality. In this review, biomanufacturing parameters encountered in planar culture and microcarrier-based bioreactor culture of hMSCs are compared and discussed with specific focus on cell-adhesion surface (e.g., discontinuous surface, underlying curvature, microcarrier stiffness, porosity, surface roughness, coating, and charge) and the dynamic microenvironment in bioreactor culture (e.g., oxygen and nutrients, shear stress, particle collision, and aggregation). The influence of dynamic culture in bioreactors on hMSC properties is also reviewed in order to establish connection between bioprocessing and stem cell function. This review addresses fundamental principles and concepts for future design of biomanufacturing systems for hMSCbased therapy.

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Section: Bioprocessing For Hmsc Productionmentioning

confidence: 99%

Influence of Microenvironment on Mesenchymal Stem Cell Therapeutic Potency: From Planar Culture to Microcarriers

Tsai

Jeske

Chen

et al. 2020

Front. Bioeng. Biotechnol.

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“…MSCs were cultured on 3D TableTrix (F01, CytoNiche Biotech, China), a tablet which disperse into a hundred thousand gelatin‐based microcarriers upon introduction to aqueous solution. [ 17 ] 5 tablets of 3D TableTrix (giving a total of 5×10 5 microcarriers) with 40 mL culture medium (M001, Viral Therapy Technologies, China) and 5 × 10 6 adipose‐derived MSCs (human) were introduced into a sterile 125 mL spinner flask (SF125, CytoNiche Biotech, China). The spinner flask was then placed on a 3D FloTrix miniSPIN system (M1, CytoNiche Biotech, China) that was set up inside a cell culture incubator (CCL1708‐8, ESCO, Singapore).…”

Section: Methodsmentioning

confidence: 99%

TGase‐Enhanced Microtissue Assembly in 3D‐Printed‐Template‐Scaffold (3D‐MAPS) for Large Tissue Defect Reparation

You

Yan³

et al. 2020

Adv Healthcare Materials

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Engineering large and functional tissue constructs with complex structures (e.g., external ear or nose) for reparation and reconstruction of tissue defects remains one of the major challenges in regenerative medicine, which demands abundant cell sources, advanced biofabrication schemes, and satisfactory integration with the host for long‐term efficacy post implantation. Here the ‘Microtissue Assembly in 3D‐Printed‐template‐Scaffold’ (3D‐MAPS), as a platform technology to rapidly fabricate centimeter‐sized functional tissue constructs with complex structures, is developed. 3D‐MAPS facilitates bottom‐up assembly of large‐scale manufactured microtissues within the 3D‐printed hollow polymeric templates with pre‐defined architectures. The assembly and fusion of 2×106 mesenchymal stem cell–based microtissues within the defined 3D‐printed template is further enhanced by addition of a natural protein crosslinker (i.e., transglutaminase (TGase)), and thereby achieves construction of centimeter‐sized tissue with high cell viability and mechanical stability in vitro within 30 min. Further in vivo implantation of the 3D‐MAPS‐fabricated ear‐like tissue construct in rabbit models assisted by flap prefabrication technique results in increased structural vascular support and strengthened functional survival. Thus, the TGase‐enhanced 3D‐MAPS demonstrates its potential and feasibility as a powerful biofabrication platform for tissue engineering application.

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“…However, if the targeting inoculum is above the scale that planar cultures can achieve, microcarrier cultures can also be incorporated into seed trains [32,59]. An intriguing alternative that simplifies the process, is the direct transfer of seeded microcarriers from the seed train stage into the scaled-up bioreactor with fresh medium and empty microcarriers [37,46]. This approach requires satisfactory cell migration from seeded beads to unseeded beads but skips the passaging processes, such as enzymatic treatment, mechanical force detachment, centrifugation and resuspension of cell pellets.…”

Section: Seed Trainmentioning

confidence: 99%

“…As shown in Table 1, the pH setpoint falls between 7 to 7.5 and the pH can be controlled by diluted base (e.g., NaOH, NaHCO 3 ) and diluted acid (e.g., H 2 SO 4 ) or CO 2 gas [27,35,36,40,43]. Two studies have successfully maintained pH merely through the use of 5% CO 2 gas [15,46]. Even though in-line pH probes must be calibrated before each use, off-line calibration (i.e., samples from culture immediately measured by off-line pH meters) enhances the measurement accuracy during cell expansion, especially for long-term cultures.…”

Section: Control System (Temperature and Ph And Do)mentioning

confidence: 99%

Bioprocessing of Human Mesenchymal Stem Cells: From Planar Culture to Microcarrier-Based Bioreactors

Tsai

Pacak

2021

Bioengineering

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Human mesenchymal stem cells (hMSCs) have demonstrated great potential to be used as therapies for many types of diseases. Due to their immunoprivileged status, allogeneic hMSCs therapies are particularly attractive options and methodologies to improve their scaling and manufacturing are needed. Microcarrier-based bioreactor systems provide higher volumetric hMSC production in automated closed systems than conventional planar cultures. However, more sophisticated bioprocesses are necessary to successfully convert from planar culture to microcarriers. This article summarizes key steps involved in the planar culture to microcarrier hMSC manufacturing scheme, from seed train, inoculation, expansion and harvest. Important bioreactor parameters, such as temperature, pH, dissolved oxygen (DO), mixing, feeding strategies and cell counting techniques, are also discussed.

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Dispersible and Dissolvable Porous Microcarrier Tablets Enable Efficient Large-Scale Human Mesenchymal Stem Cell Expansion

Cited by 50 publications

References 43 publications

Influence of Microenvironment on Mesenchymal Stem Cell Therapeutic Potency: From Planar Culture to Microcarriers

Influence of Microenvironment on Mesenchymal Stem Cell Therapeutic Potency: From Planar Culture to Microcarriers

TGase‐Enhanced Microtissue Assembly in 3D‐Printed‐Template‐Scaffold (3D‐MAPS) for Large Tissue Defect Reparation

Bioprocessing of Human Mesenchymal Stem Cells: From Planar Culture to Microcarrier-Based Bioreactors

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