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  • Review Article
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Biomanufacturing for clinically advanced cell therapies

Nature Biomedical Engineering volume 2, pages 362–376 (2018)Cite this article

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Abstract

The achievements of cell-based therapeutics have galvanized efforts to bring cell therapies to the market. To address the demands of the clinical and eventual commercial-scale production of cells, and with the increasing generation of large clinical datasets from chimeric antigen receptor T-cell immunotherapy, from transplants of engineered haematopoietic stem cells and from other promising cell therapies, an emphasis on biomanufacturing requirements becomes necessary. Robust infrastructure should address current limitations in cell harvesting, expansion, manipulation, purification, preservation and formulation, ultimately leading to successful therapy administration to patients at an acceptable cost. In this Review, we highlight case examples of cutting-edge bioprocessing technologies that improve biomanufacturing efficiency for cell therapies approaching clinical use.

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Fig. 1: Cell-therapy pharmacoeconomics and manufacture.
Fig. 2: Process optimization for the expansion of cells and for cell collection from microcarriers.
Fig. 3: Towards high-throughput label-free purification.
Fig. 4: Streamlining the genetic modification of cells for therapy.
Fig. 5: Overview of current tools for differentiating PSCs into retinal and neuronal lineages.
Fig. 6: Islet encapsulation.
Fig. 7: Supply chain for CTPs.
Fig. 8: Segmented costs for translating cell therapeutics.

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References

  1. Bianchi, M. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 114, 2619 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Grossman, M. et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat. Genet. 6, 335–341 (1994).

    CAS  PubMed  Google Scholar 

  3. Bainbridge, J. W. B. et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N. Engl. J. Med. 372, 1887–1897 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. Bennett, J. et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet 388, 661–672 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Clark, M. A., Jepson, M. A. & Hirst, B. H. Exploiting M cells for drug and vaccine delivery. Adv. Drug Deliv. Rev. 50, 81–106 (2001).

    CAS  PubMed  Google Scholar 

  6. Culme-Seymour, E. J., Davie, N. L., Brindley, D. A., Edwards-Parton, S. & Mason, C. A decade of cell therapy clinical trials (2000–2010). Regen. Med. 7, 455–462 (2012).

    CAS  PubMed  Google Scholar 

  7. National Cell Manufacturing Consortium Achieving Large-Scale, Cost-Effective, Reproducible Manufacturing of High-Quality Cells: A Technology Road Map to 2025 (Office of Science, Technology, and Policy, 2016); http://www.cellmanufacturingusa.org/sites/default/files/NCMC_Roadmap_021816_high_res-2.pdf

  8. National Science and Technology Council Advanced Manufacturing: A Snapshot of Priority Technology Areas Across the Federal Government (Office of Science and Technology Policy, 2016).

  9. Human Cells, Tissues, and Cellular and Tissue-based Products, FDA 21 CFR § 1271 (US Government Publishing Office, 2006).

  10. Lipsitz, Y. Y., Timmins, N. E. & Zandstra, P. W. Quality cell therapy manufacturing by design. Nat. Biotechnol. 34, 393–400 (2016).

    CAS  PubMed  Google Scholar 

  11. Pritchett, T. & Little, L. Hard cell: potency testing for cellular therapy products. BioProcess Int. 10, 36–48 (2012).

  12. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products (January, 2011).

  13. Castrillo, A., Cardoso, M. & Rouse, L. Treatment of buffy coat platelets in platelet additive solution with the mirasol® pathogen reduction technology system. Transfus. Med. Hemother. 40, 44–48 (2013).

    PubMed  PubMed Central  Google Scholar 

  14. Marschner, S. & Goodrich, R. Pathogen reduction technology treatment of platelets, plasma and whole blood using riboflavin and UV light. Transfus. Med. Hemother. 38, 8–18 (2011).

    PubMed  PubMed Central  Google Scholar 

  15. Wang, J. F., Wu, Y. F., Harrintong, J. & McNiece, I. K. Ex vivo expansions and transplantations of mouse bone marrow-derived hematopoietic stem/progenitor cells. J. Zhejiang Univ. Sci. 5, 157–163 (2004).

    PubMed  Google Scholar 

  16. Angelopoulou, M. et al. Cotransplantation of human mesenchymal stem cells enhances human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice. Exp. Hematol. 31, 413–420 (2003).

    CAS  PubMed  Google Scholar 

  17. Ball, L. M. et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 110, 2764–2767 (2007).

    CAS  PubMed  Google Scholar 

  18. Le Blanc, K. et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371, 1579–1586 (2008).

    PubMed  Google Scholar 

  19. Le Blanc, K. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441 (2004).

    PubMed  Google Scholar 

  20. Ringden, O. et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81, 1390–1397 (2006).

    PubMed  Google Scholar 

  21. Parekkadan, B. et al. Aire controls mesenchymal stem cell-mediated suppression in chronic colitis. Mol. Ther. 20, 178–186 (2012).

    CAS  PubMed  Google Scholar 

  22. Parekkadan, B., Tilles, A. W. & Yarmush, M. L. Bone marrow-derived mesenchymal stem cells ameliorate autoimmune enteropathy independently of regulatory T cells. Stem Cells 26, 1913–1919 (2008).

    PubMed  Google Scholar 

  23. Parekkadan, B. et al. Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes. Gastroenterology 140, 966–975 (2011).

    Google Scholar 

  24. Duijvestein, M. et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59, 1662–1669 (2010).

    PubMed  Google Scholar 

  25. Semont, A. et al. Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. Adv. Exp. Med. Biol. 585, 19–30 (2006).

    CAS  PubMed  Google Scholar 

  26. Shumakov, V. I., Onishchenko, N. A., Rasulov, M. F., Krasheninnikov, M. E. & Zaidenov, V. A. Mesenchymal bone marrow stem cells more effectively stimulate regeneration of deep burn wounds than embryonic fibroblasts. Bull. Exp. Biol. Med. 136, 192–195 (2003).

    CAS  PubMed  Google Scholar 

  27. Huang, J. et al. Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ. Res. 106, 1753–1762 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Noiseux, N. et al. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol. Ther. 14, 840–850 (2006).

    CAS  PubMed  Google Scholar 

  29. Ortiz, L. A. et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc. Natl Acad. Sci. USA 100, 8407–8411 (2003).

    CAS  Google Scholar 

  30. Gupta, N. et al. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J. Immunol. 179, 1855–1863 (2007).

    CAS  PubMed  Google Scholar 

  31. Lee, J. W. et al. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am. J. Respir. Crit. Care Med. 187, 751–760 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Matthay, M. A. et al. Therapeutic potential of mesenchymal stem cells for severe acute lung injury. Chest 138, 965–972 (2010).

    PubMed  PubMed Central  Google Scholar 

  33. Parekkadan, B. et al. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS ONE 2, e941 (2007).

    PubMed  PubMed Central  Google Scholar 

  34. van Poll, D. et al. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology 47, 1634–1643 (2008).

    PubMed  Google Scholar 

  35. Togel, F. et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am. J. Physiol. Ren. Physiol. 289, F31–42 (2005).

    Google Scholar 

  36. Elman, J. S. et al. Pharmacokinetics of natural and engineered secreted factors delivered by mesenchymal stromal cells. PLoS ONE 9, e89882 (2014).

    PubMed  PubMed Central  Google Scholar 

  37. Parekkadan, B. & Milwid, J. M. Mesenchymal stem cells as therapeutics. Annu. Rev. Biomed. Eng. 12, 87–117 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Rowley, J., Abraham, E., Campbell, A., Brandwein, H. & Oh, S. Meeting lot-size challenges of manufacturing adherent cells for therapy. BioProcess Int. 10, 7 (2012).

    Google Scholar 

  39. Lechanteur, C. et al. Clinical-scale expansion of mesenchymal stromal cells: a large banking experience. J. Transl. Med. 14, 145 (2016).

    PubMed  PubMed Central  Google Scholar 

  40. Jones, M. et al. Genetic stability of bone marrow-derived human mesenchymal stromal cells in the quantum system. Cytotherapy 15, 1323–1339 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hanley, P. J. et al. Efficient manufacturing of therapeutic mesenchymal stromal cells with the use of the quantum cell expansion system. Cytotherapy 16, 1048–1058 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Schnitzler, A. C. et al. Bioprocessing of human mesenchymal stem/stromal cells for therapeutic use: current technologies and challenges. Biochem. Eng. J. 108, 3–13 (2016).

    CAS  Google Scholar 

  43. Rafiq, Q. A., Coopman, K. & Hewitt, C. J. Scale-up of human mesenchymal stem cell culture: current technologies and future challenges. Curr. Opin. Chem. Eng. 2, 8–16 (2013).

    Google Scholar 

  44. Estrada, J. C. et al. Culture of human mesenchymal stem cells at low oxygen tension improves growth and genetic stability by activating glycolysis. Cell Death Differ. 19, 743–755 (2012).

    CAS  PubMed  Google Scholar 

  45. Sieblist, C. et al. Insights into large-scale cell-culture reactors: II. Gas-phase mixing and CO2 stripping. Biotechnol. J. 6, 1547–1556 (2011).

    CAS  PubMed  Google Scholar 

  46. Nienow, A. W. Reactor engineering in large scale animal cell culture. Cytotechnology 50, 9–33 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Tan, K. Y., Reuveny, S. & Oh, S. K. W. Recent advances in serum-free microcarrier expansion of mesenchymal stromal cells: parameters to be optimized. Biochem. Biophys. Res. Commun. 473, 769–773 (2016).

    CAS  PubMed  Google Scholar 

  48. dos Santos, F. et al. Toward a clinical-grade expansion of mesenchymal stem cells from human sources: a microcarrier-based culture system under xeno-free conditions. Tissue Eng. Part C Methods 17, 1201–1210 (2011).

    Google Scholar 

  49. Cunha, B. et al. Exploring continuous and integrated strategies for the up- and downstream processing of human mesenchymal stem cells. J. Biotechnol. 213, 97–108 (2015).

    CAS  PubMed  Google Scholar 

  50. Rafiq, Q. A., Brosnan, K. M., Coopman, K., Nienow, A. W. & Hewitt, C. J. Culture of human mesenchymal stem cells on microcarriers in a 5 l stirred-tank bioreactor. Biotechnol. Lett. 35, 1233–1245 (2013).

    CAS  PubMed  Google Scholar 

  51. Yang, H. S., Jeon, O., Bhang, S. H., Lee, S. H. & Kim, B. S. Suspension culture of mammalian cells using thermosensitive microcarrier that allows cell detachment without proteolytic enzyme treatment. Cell Transplant. 19, 1123–1132 (2010).

    PubMed  Google Scholar 

  52. Shekaran, A. et al. Biodegradable ECM-coated PCL microcarriers support scalable human early MSC expansion and in vivo bone formation. Cytotherapy 18, 1332–1344 (2016).

    CAS  PubMed  Google Scholar 

  53. Hanga, M. P. et al. Expansion of bone marrow-derived human mesenchymal stem/stromal cells (hMSCs) using a two-phase liquid/liquid system. J. Chem. Technol. Biotechnol. 92, 1577–1589 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sart, S., Tsai, A.-C., Li, Y. & Ma, T. Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications. Tissue Eng. Part B Rev. 20, 365–380 (2014).

    PubMed  Google Scholar 

  55. Dykes, J., Lenshof, A., Astrand-Grundstrom, I. B., Laurell, T. & Scheding, S. Efficient removal of platelets from peripheral blood progenitor cell products using a novel micro-chip based acoustophoretic platform. PLoS ONE 6, e23074 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lupu, M., Gooley, T., Zellmer, E., Graves, S. S. & Storb, R. Principles of peripheral blood mononuclear cell apheresis in a preclinical canine model of hematopoietic cell transplantation. J. Vet. Intern. Med. 22, 74–82 (2008).

    CAS  PubMed  Google Scholar 

  57. The dose makes the poison. Nat. Nanotech. 6, 329 (2011).

  58. Perin, E. C. et al. A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ. Res. 117, 576–584 (2015).

    CAS  PubMed  Google Scholar 

  59. Hatch, A., Hansmann, G. & Murthy, S. K. Engineered alginate hydrogels for effective microfluidic capture and release of endothelial progenitor cells from whole blood. Langmuir 27, 4257–4264 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, B. L. et al. Microfluidic high-throughput culturing of single cells for selection based on extracellular metabolite production or consumption. Nat. Biotechnol. 32, 473–478 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Chabert, M. & Viovy, J.-L. Microfluidic high-throughput encapsulation and hydrodynamic self-sorting of single cells. Proc. Natl Acad. Sci. USA 105, 3191–3196 (2008).

  62. A safety, tolerability, and efficacy study of VC-01™ combination product in subjects with type I diabetes mellitus. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/results/NCT02239354 (2015).

  63. Hsu, C. H., Chen, C., Irimia, D. & Toner, M. Fast sorting of CD4+ T cells from whole blood using glass microbubbles. Technology (Singap. World Sci.) 3, 38–44 (2015).

  64. Toner, M. & Irimia, D. Blood-on-a-chip. Annu. Rev. Biomed. Eng. 7, 77–103 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sethu, P. et al. Microfluidic isolation of leukocytes from whole blood for phenotype and gene expression analysis. Anal. Chem. 78, 5453–5461 (2006).

    CAS  PubMed  Google Scholar 

  66. Simon, M. G. et al. Increasing label-free stem cell sorting capacity to reach transplantation-scale throughput. Biomicrofluidics 8, 064106 (2014).

    PubMed  PubMed Central  Google Scholar 

  67. Nakamura, H. & Funahashi, J. Electroporation: past, present and future. Dev. Growth Differ. 55, 15–19 (2013).

    PubMed  Google Scholar 

  68. Zhao, Y. et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70, 9053–9061 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Jin, Z. et al. The hyperactive Sleeping Beauty transposase SB100X improves the genetic modification of T cells to express a chimeric antigen receptor. Gene Ther. 18, 849–856 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Raja Manuri, P. V. et al. piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. Hum. Gene Ther. 21, 427–437 (2010).

    CAS  PubMed  Google Scholar 

  71. Saito, S. et al. Anti-leukemic potency of piggyBac-mediated CD19-specific T cells against refractory Philadelphia chromosome–positive acute lymphoblastic leukemia. Cytotherapy 16, 1257–1269 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ramanayake, S. et al. Low-cost generation of Good Manufacturing Practice-grade CD19-specific chimeric antigen receptor–expressing T cells using piggyBac gene transfer and patient-derived materials. Cytotherapy 17, 1251–1267 (2015).

    CAS  PubMed  Google Scholar 

  73. van der Loo, J. C. & Wright, J. F. Progress and challenges in viral vector manufacturing. Hum. Mol. Genet. 25, R42–R52 (2016).

    PubMed  Google Scholar 

  74. Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Sadelain, M. CD19 CAR T cells. Cell 171, 1471 (2017).

    CAS  PubMed  Google Scholar 

  76. Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

  77. Lynn, R. C. et al. High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity. Leukemia 30, 1355–1364 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Maus, M. V. & June, C. H. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin. Cancer Res. 22, 1875–1884 (2016).

  79. Zhang, B. et al. The significance of controlled conditions in lentiviral vector titration and in the use of multiplicity of infection (MOI) for predicting gene transfer events. Genet. Vaccin. Ther. 2, 6 (2004).

    Google Scholar 

  80. Eichler, F. et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N. Engl. J. Med. 377, 1630–1638 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Thrasher, A. J. & Williams, D. A. Evolving gene therapy in primary immunodeficiency. Mol. Ther. 25, 1132–1141 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Hacein-Bey-Abina, S. et al. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N. Engl. J. Med. 371, 1407–1417 (2014).

    PubMed  PubMed Central  Google Scholar 

  83. Wu, C. & Dunbar, C. E. Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity. Front. Med. 5, 356–371 (2011).

    PubMed  PubMed Central  Google Scholar 

  84. Singh, N., Shi, J., June, C. H. & Ruella, M. Genome-editing technologies in adoptive T cell immunotherapy for cancer. Curr. Hematol. Malig. Rep. 12, 522–529 (2017).

    PubMed  PubMed Central  Google Scholar 

  85. Moore, J. C. et al. Efficient, high-throughput transfection of human embryonic stem cells. Stem Cell Res. Ther. 1, 23 (2010).

    PubMed  PubMed Central  Google Scholar 

  86. Li, L. H. et al. Rapid and efficient nonviral gene delivery of CD154 to primary chronic lymphocytic leukemia cells. Cancer Gene. Ther. 13, 215–224 (2006).

    CAS  PubMed  Google Scholar 

  87. Li, L. H. et al. Highly efficient, large volume flow electroporation. Technol. Cancer Res. Treat. 1, 341–350 (2002).

    CAS  PubMed  Google Scholar 

  88. Fratantoni, J. C., Dzekunov, S., Singh, V. & Liu, L. N. A non-viral gene delivery system designed for clinical use. Cytotherapy 5, 208–210 (2003).

    CAS  PubMed  Google Scholar 

  89. Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).

    CAS  PubMed  Google Scholar 

  90. Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).

    PubMed  PubMed Central  Google Scholar 

  91. Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).

    CAS  PubMed  Google Scholar 

  92. Sharei, A. et al. Cell squeezing as a robust, microfluidic intracellular delivery platform. J. Vis. Exp. 81, e50980 (2013).

  93. Kim, J. A. et al. A novel electroporation method using a capillary and wire-type electrode. Biosens. Bioelectron. 23, 1353–1360 (2008).

    CAS  PubMed  Google Scholar 

  94. O’Dea, S. et al. Vector-free intracellular delivery by reversible permeabilization. PLoS ONE 12, e0174779 (2017).

    PubMed  PubMed Central  Google Scholar 

  95. Yang, F. et al. Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles. Proc. Natl Acad. Sci. USA 107, 3317–3322 (2010).

    Google Scholar 

  96. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  97. Scudellari, M. How iPS cells changed the world. Nature 534, 310 (2016).

    PubMed  Google Scholar 

  98. Di Foggia, V., Makwana, P., Ali, R. R. & Sowden, J. C. Induced pluripotent stem cell therapies for degenerative disease of the outer retina: disease modeling and cell replacement. J. Ocul. Pharmacol. Ther. 32, 240–252 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. Focosi, D. et al. Induced pluripotent stem cells in hematology: current and future applications. Blood Cancer J. 4, e211 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Imaizumi, Y. & Okano, H. Modeling human neurological disorders with induced pluripotent stem cells. J. Neurochem. 129, 388–399 (2014).

    CAS  PubMed  Google Scholar 

  101. Vaccarino, F. M. et al. Annual research review: the promise of stem cell research for neuropsychiatric disorders. J. Child Psychol. Psychiatry 52, 504–516 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. Haggarty, S. J., Silva, M. C., Cross, A., Brandon, N. J. & Perlis, R. H. Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models. Mol. Cell. Neurosci. 73, 104–115 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Bravery, C. A. Do human leukocyte antigen-typed cellular therapeutics based on induced pluripotent stem cells make commercial sense? Stem Cells Dev. 24, 1–10 (2015).

    PubMed  Google Scholar 

  104. Jacquet, L. et al. Strategy for the creation of clinical grade hESC line banks that HLA-match a target population. EMBO Mol. Med. 5, 10–17 (2013).

    CAS  PubMed  Google Scholar 

  105. Fusaki, N., Ban, H., Nishiyama, A., Saeki, K. & Hasegawa, M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 85, 348–362 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Sridhar, A., Ohlemacher, S. K., Langer, K. B. & Meyer, J. S. Robust differentiation of mRNA-reprogrammed human induced pluripotent stem cells toward a retinal lineage. Stem Cells Transl. Med. 5, 417–426 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Jenkins, M. J. & Farid, S. S. Human pluripotent stem cell-derived products: advances towards robust, scalable and cost-effective manufacturing strategies. Biotechnol. J. 10, 83–95 (2015).

    CAS  PubMed  Google Scholar 

  109. Lin, H., Li, Q. & Lei, Y. An integrated miniature bioprocessing for personalized human induced pluripotent stem cell expansion and differentiation into neural stem cells. Sci. Rep. 7, 40191 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Serra, M., Brito, C., Correia, C. & Alves, P. M. Process engineering of human pluripotent stem cells for clinical application. Trends Biotechnol. 30, 350–359 (2012).

    CAS  PubMed  Google Scholar 

  111. Hong, S. G., Dunbar, C. E. & Winkler, T. Assessing the risks of genotoxicity in the therapeutic development of induced pluripotent stem cells. Mol. Ther. 21, 272–281 (2013).

    CAS  PubMed  Google Scholar 

  112. Nguyen, H. T., Geens, M. & Spits, C. Genetic and epigenetic instability in human pluripotent stem cells. Hum. Reprod. Update 19, 187–205 (2013).

    CAS  PubMed  Google Scholar 

  113. Lund, R. J., Narva, E. & Lahesmaa, R. Genetic and epigenetic stability of human pluripotent stem cells. Nat. Rev. Genet. 13, 732–744 (2012).

    CAS  PubMed  Google Scholar 

  114. Trainor, N., Pietak, A. & Smith, T. Rethinking clinical delivery of adult stem cell therapies. Nat. Biotechnol. 32, 729 (2014).

    CAS  PubMed  Google Scholar 

  115. Lipsitz, Y. Y., Timmins, N. E. & Zandstra, P. W. Quality cell therapy manufacturing by design. Nat. Biotechnol. 34, 393–400 (2016).

    CAS  PubMed  Google Scholar 

  116. Choudhary, P. et al. Directing differentiation of pluripotent stem cells toward retinal pigment epithelium lineage. Stem Cells Transl. Med. 6, 490–501 (2017).

    CAS  PubMed  Google Scholar 

  117. Ding, S. et al. Synthetic small molecules that control stem cell fate. Proc. Natl Acad. Sci. USA 100, 7632–7637 (2003).

    CAS  Google Scholar 

  118. Saxena, P. et al. A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells. Nat. Commun. 7, 11247 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kamat, V. et al. MicroRNA screen of human embryonic stem cell differentiation reveals miR-105 as an enhancer of megakaryopoiesis from adult CD34+ cells. Stem Cells 32, 1337–1346 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Yu, Z., Li, Y., Fan, H., Liu, Z. & Pestell, R. miRNAs regulate stem cell self-renewal and differentiation. Front. Genet. 3, 191 (2012).

  121. Jiang, C. et al. MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway. Oncotarget 7, 52340–52353 (2016).

    PubMed  PubMed Central  Google Scholar 

  122. Loewer, S. et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat. Genet. 42, 1113–1117 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Li, M. et al. Phenotypic and functional characterization of human bone marrow stromal cells in hollow-fibre bioreactors. J. Tissue Eng. Regen. Med. 6, 369–377 (2012).

    CAS  PubMed  Google Scholar 

  124. Yagi, H. et al. Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure. Tissue Eng. Part A 15, 3377–3388 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. de Vos, P. et al. Multiscale requirements for bioencapsulation in medicine and biotechnology. Biomaterials 30, 2559–2570 (2009).

    PubMed  Google Scholar 

  126. Rokstad, A. M. A., Lacik, I., de Vos, P. & Strand, B. L. Advances in biocompatibility and physico-chemical characterization of microspheres for cell encapsulation. Adv. Drug Deliv. Rev. 67–68, 111–130 (2014).

    PubMed  Google Scholar 

  127. National Diabetes Statistics Report, 2014: Estimates of Diabetes and its Burden in the United States (Center for Disease Control and Prevention, 2014).

  128. Qi, M. Transplantation of encapsulated pancreatic islets as a treatment for patients with type 1 diabetes mellitus. Adv. Med. 2014, 429710 (2014).

  129. Desai, T. & Shea, L. D. Advances in islet encapsulation technologies. Nat. Rev. Drug Discov. 16, 338–350 (2016).

  130. Scharp, D. W. & Marchetti, P. Encapsulated islets for diabetes therapy: history, current progress, and critical issues requiring solution. Adv. Drug Deliv. Rev. 67–68, 35–73 (2014).

    PubMed  Google Scholar 

  131. Shapiro, A. et al. Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome. Rev. Diabet. Stud. 9, 385–406 (2012).

    PubMed  Google Scholar 

  132. Hrvatin, S. et al. Differentiated human stem cells resemble fetal, not adult, β cells. Proc. Natl Acad. Sci. USA 111, 3038–3043 (2014).

    CAS  Google Scholar 

  133. Pagliuca, F. W. et al. Generation of functional human pancreatic β cells in vitro. Cell 159, 428–439 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. O’Sullivan, E. S., Vegas, A., Anderson, D. G. & Weir, G. C. Islets transplanted in immunoisolation devices: a review of the progress and the challenges that remain. Endocr. Rev. 32, 827–844 (2011).

    PubMed  PubMed Central  Google Scholar 

  135. Open-label investigation of the safety and effectiveness of DIABECELL(R) in patients with type I diabetes mellitus. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00940173 (2014).

  136. Open-label investigation of the safety and efficacy of DIABECELL in patients with type 1 diabetes mellitus. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01736228 (2015).

  137. Barkai, U. et al. Enhanced oxygen supply improves islet viability in a new bioartificial pancreas. Cell Transplant. 22, 1463–1476 (2013).

    PubMed  Google Scholar 

  138. Neufeld, T. et al. The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs. PLoS ONE 8, e70150 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ludwig, B. et al. Transplantation of human islets without immunosuppression. Proc. Natl Acad. Sci. USA 110, 19054–19058 (2013).

    CAS  Google Scholar 

  140. Ludwig, B. et al. A novel device for islet transplantation providing immune protection and oxygen supply. Horm. Metab. Res. 42, 918–922 (2010).

    CAS  PubMed  Google Scholar 

  141. Ludwig, B. et al. Islet transplantation at the Dresden diabetes center: five years’ experience. Horm. Metab. Res. 47, 4–8 (2015).

    CAS  PubMed  Google Scholar 

  142. Pepper, A. R. et al. Diabetes is reversed in a murine model by marginal mass syngeneic islet transplantation using a subcutaneous cell pouch device. Transplantation 99, 2294–2300 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. A phase I/II study of the safety and efficacy of Sernova’s Cell PouchTM for therapeutic islet transplantation ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01652911 (2016).

  144. Tuch, B. E. et al. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care 32, 1887–1889 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. de Groot, M., Schuurs, T. A. & van Schilfgaarde, R. Causes of limited survival of microencapsulated pancreatic islet grafts. J. Surg. Res. 121, 141–150 (2004).

    PubMed  Google Scholar 

  146. Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345–352 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Vegas, A. J. et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat. Med. 22, 306–311 (2016).

  148. Martín-Banderas, L. et al. Making drops in microencapsulation processes. Lett. Drug Des. Discov. 7, 300–309 (2010).

    Google Scholar 

  149. Hunt, C. J. Cryopreservation of human stem cells for clinical application: a review. Transfus. Med. Hemother. 38, 107–123 (2011).

    PubMed  PubMed Central  Google Scholar 

  150. Sauer-Heilborn, A., Kadidlo, D. & McCullough, J. Patient care during infusion of hematopoietic progenitor cells. Transfusion 44, 907–916 (2004).

    PubMed  Google Scholar 

  151. Khera, N. et al. Limiting the daily total nucleated cell dose of cryopreserved peripheral blood stem cell products for autologous transplantation improves infusion-related safety with no adverse impact on hematopoietic engraftment. Biol. Blood Marrow Transplant. 18, 220–228 (2012).

    PubMed  Google Scholar 

  152. Best, B. P. Cryoprotectant toxicity: facts, issues, and questions. Rejuvenation Res 18, 422–436 (2015).

    PubMed  PubMed Central  Google Scholar 

  153. Song, Y. S. et al. Microfluidics for cryopreservation. Lab Chip 9, 1874–1881 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Buchanan, S. S. et al. Cryopreservation of stem cells using trehalose: evaluation of the method using a human hematopoietic cell line. Stem Cells Dev. 13, 295–305 (2004).

    CAS  PubMed  Google Scholar 

  155. Eroglu, A. et al. Intracellular trehalose improves the survival of cryopreserved mammalian cells. Nat. Biotechnol. 18, 163–167 (2000).

    CAS  PubMed  Google Scholar 

  156. Thirumala, S., Wu, X., Gimble, J. M. & Devireddy, R. V. Evaluation of polyvinylpyrrolidone as a cryoprotectant for adipose tissue-derived adult stem cells. Tissue Eng. Part C Methods 16, 783–792 (2010).

  157. Shivakumar, S. B. et al. Cryopreservation of human Wharton’s jelly-derived mesenchymal stem cells following controlled rate freezing protocol using different cryoprotectants; a comparative study. Int. J. Stem Cells 8, 155–169 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Miyamoto, Y. et al. Cryopreservation of human adipose tissue-derived stem/progenitor cells using the silk protein sericin. Cell Transplant. 21, 617–622 (2012).

    PubMed  Google Scholar 

  159. Moll, G. et al. Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells 32, 2430–2442 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Robinson, N. J., Picken, A. & Coopman, K. Low temperature cell pausing: an alternative short-term preservation method for use in cell therapies including stem cell applications. Biotechnol. Lett. 36, 201–209 (2014).

    CAS  PubMed  Google Scholar 

  161. Lipsitz, Y. Y. et al. A roadmap for cost-of-goods planning to guide economic production of cell therapy products. Cytotherapy 19, 1383–1391 (2017).

    PubMed  Google Scholar 

  162. Hassan, S. et al. Allogeneic cell therapy bioprocess economics and optimization: downstream processing decisions. Regen. Med. 10, 591–609 (2015).

    CAS  PubMed  Google Scholar 

  163. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank a number of colleagues for feedback on a draft of the manuscript, specifically B. Hampson and T. Heathman from Hitachi Chemical Advanced Therapeutics Solutions. This work was supported in part by the Shriners Hospitals for Children (B.P.) and by the National Institutes of Health Grant R01EB012521 (B.P.).

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Author notes

  1. These authors contributed equally: Ayesha Aijaz, Matthew Li, David Smith.

Authors and Affiliations

  1. Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA

    Ayesha Aijaz, Ronke M. Olabisi & Biju Parekkadan

  2. Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, MA, USA

    Matthew Li, Danika Khong & Biju Parekkadan

  3. Hitachi Chemical Advanced Therapeutics Solutions, Allendale, NJ, USA

    David Smith, Courtney LeBlon & Robert Preti

  4. Department of Chemical Engineering, Institute for Medical Engineering and Science, Division of Health Science and Technology, and the David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Owen S. Fenton & Daniel G. Anderson

  5. Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Steven Libutti

  6. Human Genetics Institute of New Jersey, RUCDR, Piscataway, NJ, USA

    Jay Tischfield

  7. Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Marcela V. Maus

  8. BlueRock Therapeutics, Cambridge, MA, USA

    Robert Deans

  9. Sentien Biotechnologies, Inc, Lexington, MA, USA

    Rita N. Barcia & Biju Parekkadan

  10. Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Jerome Ritz

  11. Harvard Stem Cell Institute, Cambridge, MA, USA

    Jerome Ritz & Biju Parekkadan

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Contributions

All authors contributed to the writing of subsections of the manuscript. A.A., M.L., D.S., R.P. and B.P. contributed to all sections and to figure preparation. D.K., J.T. and R.D. contributed to the content relevant to iPSCs and ESCs. C.L. contributed to content on biopreservation. O.S.F., R.M.O. and D.G.A. contributed to the discussion of cell–material composites. S.L., M.V.M. and J.R. contributed to the cell-engineering discussion. R.N.B. contributed to the content on cell expansion.

Corresponding author

Correspondence to Biju Parekkadan.

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Competing interests

A.A., M.L., O.S.F., D.K., M.V.M., J.R., J.T., R.M.O. and S.L. declare no competing interests. D.S., C.L. and R.P. are employees of Hitachi Chemical Advanced Therapeutics Solutions. R.D. owns equity in BlueRock Therapeutics. D.G.A. is a founder and equity shareholder in Siglion Therapeutics. R.N.B. is an employee and equity shareholder of Sentien Biotechnologies, Inc. B.P. is a founder and equity shareholder of Sentien Biotechnologies, Inc.

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Phase-II and Phase-III clinical trials that include the use of cell therapies

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Aijaz, A., Li, M., Smith, D. et al. Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng 2, 362–376 (2018). https://doi.org/10.1038/s41551-018-0246-6

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