NDLI: Identifying and optimizing critical process parameters for large-scale manufacturing of iPSC derived insulin-producing β-cells

Content Provider	Springer Nature : BioMed Central
Author	Yehya, Haneen Wells, Alexandra Majcher, Michael Nakhwa, Dhruv King, Ryan Senturk, Faruk Padmanabhan, Roshan Jensen, Jan Bukys, Michael A.
Abstract	Background Type 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture. Methods We examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors. Results A three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies. Conclusion This study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.
Related Links	https://stemcellres.biomedcentral.com/counter/pdf/10.1186/s13287-024-03973-0.pdf
Ending Page	24
Page Count	24
Starting Page	1
File Format	HTM / HTML
ISSN	17576512
DOI	10.1186/s13287-024-03973-0
Journal	Stem Cell Research & Therapy
Issue Number	1
Volume Number	15
Language	English
Publisher	BioMed Central
Publisher Date	2024-11-09
Access Restriction	Open
Subject Keyword	Stem Cells Cell Biology Regenerative Medicine Tissue Engineering Biomedical Engineering and Bioengineering Diabetes Human induced pluripotent stem cell Insulin producing cells Bioreactor DoE β-cells Pancreatic cells Bioprocess development Optimization Islets iPSCs Regenerative Medicine/Tissue Engineering
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Biochemistry, Genetics and Molecular Biology Molecular Medicine
Journal Impact Factor	7.1/2023
5-Year Journal Impact Factor	7.9/2023

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