Large-Scale Mesenchymal Stem/Stromal Cell Expansion: A Visualization Tool for Bioprocess Comparison.

Large-scale and cost-effective cell expansion processes are a prerequisite for the clinical and commercial translation of cell-based therapies. A large variety of cell expansion processes are described in literature, utilizing different cell types, culture vessels, and medium formulations. Consequently there are no straightforward means for the comparison or benchmarking of these processes in terms of efficiency, scale, or costs. The purpose of this study was to systematically review the available mesenchymal stromal cell (MSC) expansion literature and develop an interactive visualization tool for comparing the expansion processes. By using this computational tool, process data could be concentrated, standardized, and analyzed to facilitate a more general understanding of the parameters that define a cell culture process, and in the future allow rational selection or design of these bioprocesses. Additionally, a set of bioprocess metrics were defined that assured the comparability between different processes. Currently, the literature-based data repository holds 73 individual cell expansion processes on seven different types of human MSCs in five different types of culture vessels. The visualization tool allowed benchmarking of these processes against each other, serving as a reference point for cell expansion process efficiency.

[1]  Elie Dolgin Better standards sought for range of stem cells entering the clinic , 2014, Nature Medicine.

[2]  L. Rosenberg,et al.  Large‐scale production of human mesenchymal stem cells for clinical applications , 2012, Biotechnology and applied biochemistry.

[3]  Robert Deans Towards the creation of a standard MSC line as a calibration tool. , 2015, Cytotherapy.

[4]  C. Hewitt,et al.  Agitation conditions for the culture and detachment of hMSCs from microcarriers in multiple bioreactor platforms , 2016 .

[5]  A. S. Simaria,et al.  Allogeneic Cell Therapy Bioprocess Economics and Optimization: Single-Use Cell Expansion Technologies , 2013, Biotechnology and bioengineering.

[6]  R. Seetharam,et al.  Serum‐free media for the production of human mesenchymal stromal cells: a review , 2013, Cell proliferation.

[7]  Wolfgang Henrich,et al.  Large Scale Expansion of Human Umbilical Cord Cells in a Rotating Bed System Bioreactor for Cardiovascular Tissue Engineering Applications , 2013, The open biomedical engineering journal.

[8]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.

[9]  J. Schrooten,et al.  Model‐based cell number quantification using online single‐oxygen sensor data for tissue engineering perfusion bioreactors , 2014, Biotechnology and bioengineering.

[10]  Setsuya Aiba,et al.  Human adipose tissue possesses a unique population of pluripotent stem cells with nontumorigenic and low telomerase activities: potential implications in regenerative medicine. , 2014, Stem cells and development.

[11]  ViswanathanSowmya,et al.  Soliciting strategies for developing cell-based reference materials to advance mesenchymal stromal cell research and clinical translation. , 2014 .

[12]  Bo Kara,et al.  The translation of cell-based therapies: clinical landscape and manufacturing challenges. , 2015, Regenerative medicine.

[13]  Anna French,et al.  Reference materials for cellular therapeutics. , 2014, Cytotherapy.

[14]  Paula M. Alves,et al.  Filtration methodologies for the clarification and concentration of human mesenchymal stem cells , 2015 .

[15]  Suzanne S Farid,et al.  Human pluripotent stem cell-derived products: Advances towards robust, scalable and cost-effective manufacturing strategies , 2014, Biotechnology journal.

[16]  Jean-Marie Aerts,et al.  Real-time characterisation of the harvesting process for adherent mesenchymal stem cell cultures based on on-line imaging and model-based monitoring , 2015 .

[17]  L.Y. Sun,et al.  Cell proliferation of human bone marrow mesenchymal stem cells on biodegradable microcarriers enhances in vitro differentiation potential , 2010, Cell proliferation.

[18]  Bo Kara,et al.  Expansion, harvest and cryopreservation of human mesenchymal stem cells in a serum‐free microcarrier process , 2015, Biotechnology and bioengineering.

[19]  Chris Mason,et al.  Cell Therapy Regulatory Toolkit: an online regulatory resource. , 2015, Regenerative medicine.

[20]  Jean-Marie Aerts,et al.  Large-scale progenitor cell expansion for multiple donors in a monitored hollow fibre bioreactor. , 2016, Cytotherapy.

[21]  J. R. Smith,et al.  Manufacturing of Human Umbilical Cord Mesenchymal Stromal Cells on Microcarriers in a Dynamic System for Clinical Use , 2016, Stem cells international.

[22]  F. Luyten,et al.  Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. , 2001, Arthritis and rheumatism.

[23]  J. Gimble,et al.  Toward a clinical-grade expansion of mesenchymal stem cells from human sources: a microcarrier-based culture system under xeno-free conditions. , 2011, Tissue engineering. Part C, Methods.

[24]  M. Varella‐Garcia,et al.  Genetic stability of bone marrow-derived human mesenchymal stromal cells in the Quantum System. , 2013, Cytotherapy.

[25]  Marta M. Silva,et al.  Production of oncolytic adenovirus and human mesenchymal stem cells in a single‐use, Vertical‐Wheel bioreactor system: Impact of bioreactor design on performance of microcarrier‐based cell culture processes , 2015, Biotechnology progress.

[26]  Margarida Serra,et al.  Improving washing strategies of human mesenchymal stem cells using negative mode expanded bed chromatography. , 2016, Journal of chromatography. A.

[27]  D. Covas,et al.  Growth and functional harvesting of human mesenchymal stromal cells cultured on a microcarrier‐based system , 2014, Biotechnology progress.

[28]  Dirk Strunk,et al.  Two steps to functional mesenchymal stromal cells for clinical application , 2007, Transfusion.

[29]  D. Eibl,et al.  Scale‐up of adipose tissue‐derived mesenchymal stem cell production in stirred single‐use bioreactors under low‐serum conditions , 2014 .

[30]  Jacques Galipeau,et al.  The mesenchymal stromal cells dilemma--does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? , 2013, Cytotherapy.

[31]  P. Bianco,et al.  Mesenchymal stem cells: revisiting history, concepts, and assays. , 2008, Cell stem cell.

[32]  Simon Edwards-Parton,et al.  A new cell therapy sector arising from the convergence of cell and gene therapy , 2013 .

[33]  Ludwika Kreja,et al.  GMP-Compliant Isolation and Expansion of Bone Marrow-Derived MSCs in the Closed, Automated Device Quantum Cell Expansion System , 2013, Cell transplantation.

[34]  Karl Kashofer,et al.  Human platelet lysate can replace fetal bovine serum for clinical‐scale expansion of functional mesenchymal stromal cells , 2007, Transfusion.

[35]  Farlan S. Veraitch,et al.  A novel filtration device for point of care preparation of cellular therapies , 2015 .

[36]  M. Choolani,et al.  Serum-free media formulations are cell line-specific and require optimization for microcarrier culture. , 2015, Cytotherapy.

[37]  Farhaan Vahidy,et al.  Efficient manufacturing of therapeutic mesenchymal stromal cells with the use of the Quantum Cell Expansion System. , 2014, Cytotherapy.

[38]  C. Hewitt,et al.  Characterization of human mesenchymal stem cells from multiple donors and the implications for large scale bioprocess development , 2016 .

[39]  Amit Chandra,et al.  Manufacturing models permitting roll out/scale out of clinically led autologous cell therapies: regulatory and scientific challenges for comparability. , 2014, Cytotherapy.

[40]  F. Luyten,et al.  Multipotent mesenchymal stem cells from adult human synovial membrane. , 2001, Arthritis and rheumatism.

[41]  Andreas Reinisch,et al.  Humanized system to propagate cord blood-derived multipotent mesenchymal stromal cells for clinical application. , 2007, Regenerative medicine.

[42]  Matthias Kraume,et al.  Microcarrier-based Expansion Process for hMSCs with High Vitality and Undifferentiated Characteristics , 2012, The International journal of artificial organs.

[43]  T. Ma,et al.  Biomanufacturing of human mesenchymal stem cells in cell therapy: Influence of microenvironment on scalable expansion in bioreactors , 2016 .

[44]  Maria Margarida Diogo,et al.  Separation technologies for stem cell bioprocessing , 2012, Biotechnology and bioengineering.

[45]  Clemens A van Blitterswijk,et al.  The effect of bone marrow aspiration strategy on the yield and quality of human mesenchymal stem cells , 2009, Acta orthopaedica.

[46]  Marta M. Silva,et al.  Exploring continuous and integrated strategies for the up- and downstream processing of human mesenchymal stem cells. , 2015, Journal of biotechnology.

[47]  S. Agathos,et al.  Engineering stem cell fate with biochemical and biomechanical properties of microcarriers , 2013, Biotechnology progress.

[48]  C. Hewitt,et al.  Culture of human mesenchymal stem cells on microcarriers in a 5 l stirred-tank bioreactor , 2013, Biotechnology Letters.

[49]  Karen Bieback,et al.  Expansion of Mesenchymal Stem/Stromal cells under xenogenic-free culture conditions. , 2013, Advances in biochemical engineering/biotechnology.

[50]  Binil Starly,et al.  Large scale industrialized cell expansion: producing the critical raw material for biofabrication processes , 2015, Biofabrication.

[51]  M. Choolani,et al.  Microcarrier Culture for Efficient Expansion and Osteogenic Differentiation of Human Fetal Mesenchymal Stem Cells , 2013, BioResearch open access.

[52]  J. Aerts,et al.  Evaluation of a monitored multiplate bioreactor for large-scale expansion of human periosteum derived stem cells for bone tissue engineering applications , 2016 .

[53]  Robert J. Thomas,et al.  Expansion of human mesenchymal stem cells on microcarriers , 2011, Biotechnology Letters.

[54]  R. Orentas,et al.  Towards a commercial process for the manufacture of genetically modified T cells for therapy , 2015, Cancer Gene Therapy.

[55]  Ilona Reischl,et al.  Manufacturing, characterization and control of cell-based medicinal products: challenging paradigms toward commercial use. , 2015, Regenerative medicine.

[56]  D. Harris,et al.  Umbilical cord blood: a unique source of pluripotent stem cells for regenerative medicine. , 2007, Current stem cell research & therapy.

[57]  Ralf Pörtner,et al.  Expansion of Human Mesenchymal Stem Cells in a Fixed-Bed Bioreactor System Based on Non-Porous Glass Carrier – Part A: Inoculation, Cultivation, and Cell Harvest Procedures , 2010, The International journal of artificial organs.

[58]  A. Ignatius,et al.  GMP-Compliant Isolation and Large-Scale Expansion of Bone Marrow-Derived MSC , 2012, PloS one.

[59]  R. Puri,et al.  MSC-based product characterization for clinical trials: an FDA perspective. , 2014, Cell stem cell.

[60]  Knut Niss,et al.  hMSC Production in Disposable Bioreactors with Regards to GMP and PAT , 2013 .

[61]  J. Schrooten,et al.  Bioreactor-Based Online Recovery of Human Progenitor Cells with Uncompromised Regenerative Potential: A Bone Tissue Engineering Perspective , 2015, PloS one.

[62]  David McKenna,et al.  Correspondence to: soliciting strategies for developing cell-based reference materials to advance mesenchymal stem/stromal cell research and clinical translation. , 2014, Stem cells and development.

[63]  Teng Ma,et al.  Expansion of human mesenchymal stem cells in fibrous bed bioreactor , 2016 .

[64]  B. Larson,et al.  Sox11 is expressed in early progenitor human multipotent stromal cells and decreases with extensive expansion of the cells. , 2010, Tissue engineering. Part A.

[65]  M. Hervy,et al.  Long Term Expansion of Bone Marrow-Derived hMSCs on Novel Synthetic Microcarriers in Xeno-Free, Defined Conditions , 2014, PloS one.

[66]  Gregor Bein,et al.  Good manufacturing practice-compliant animal-free expansion of human bone marrow derived mesenchymal stroma cells in a closed hollow-fiber-based bioreactor. , 2013, Biochemical and biophysical research communications.

[67]  J. Gimble,et al.  A xenogeneic‐free bioreactor system for the clinical‐scale expansion of human mesenchymal stem/stromal cells , 2014, Biotechnology and bioengineering.

[68]  Allison Hubel,et al.  Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices , 2014, Transfusion.

[69]  F J van Milligen,et al.  Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. , 2006, Cytotherapy.

[70]  S. Perez,et al.  Characterization of the Optimal Culture Conditions for Clinical Scale Production of Human Mesenchymal Stem Cells , 2006, Stem cells.

[71]  S. Reuveny,et al.  Recent advances in serum-free microcarrier expansion of mesenchymal stromal cells: Parameters to be optimized. , 2016, Biochemical and biophysical research communications.

[72]  Peter W Zandstra,et al.  Real-Time Monitoring and Control of Soluble Signaling Factors Enables Enhanced Progenitor Cell Outputs from Human Cord Blood Stem Cell Cultures , 2013, Biotechnology and bioengineering.

[73]  Nicholas E. Timmins,et al.  Clinical scale ex vivo manufacture of neutrophils from hematopoietic progenitor cells , 2009, Biotechnology and bioengineering.

[74]  Alvin W. Nienow,et al.  A potentially scalable method for the harvesting of hMSCs from microcarriers , 2014 .

[75]  R. Valgardsdottir,et al.  Clinical grade expansion of MSCs. , 2015, Immunology letters.

[76]  Stefano Baila,et al.  Large-Scale Clinical Expansion of Mesenchymal Stem Cells in the GMP-Compliant, Closed Automated Quantum ® Cell Expansion System: Comparison with Expansion in Traditional T-Flasks , 2014 .

[77]  Alan Trounson,et al.  Stem Cell Therapies in Clinical Trials: Progress and Challenges. , 2015, Cell stem cell.

[78]  Sally Hassan,et al.  Allogeneic cell therapy bioprocess economics and optimization: downstream processing decisions. , 2015, Regenerative medicine.

[79]  P. Andrade,et al.  Maximizing the ex vivo expansion of human mesenchymal stem cells using a microcarrier-based stirred culture system. , 2010, Journal of biotechnology.

[80]  Matthias P. Lutolf Instructing stem cell fate by engineered niches , 2014 .

[81]  Christopher A Bravery,et al.  Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry. , 2013, Cytotherapy.

[82]  D. Eibl,et al.  Modification and qualification of a stirred single-use bioreactor for the improved expansion of human mesenchymal stem cells at benchtop scale , 2014 .

[83]  S. Reuveny,et al.  Increasing efficiency of human mesenchymal stromal cell culture by optimization of microcarrier concentration and design of medium feed. , 2015, Cytotherapy.