Skip to main content
SpringerLink
Log in

Microfluidic Devices as Process Development Tools for Cellular Therapy Manufacturing

  • Chapter
  • First Online:
Microfluidics in Biotechnology

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 179))

Abstract

Cellular therapies are creating a paradigm shift in the biomanufacturing industry. Particularly for autologous therapies, small-scale processing methods are better suited than the large-scale approaches that are traditionally employed in the industry. Current small-scale methods for manufacturing personalized cell therapies, however, are labour-intensive and involve a number of ‘open events’. To overcome these challenges, new cell manufacturing platforms following a GMP-in-a-box concept have recently come on the market (GMP: Good Manufacturing Practice). These are closed automated systems with built-in pumps for fluid handling and sensors for in-process monitoring. At a much smaller scale, microfluidic devices exhibit many of the same features as current GMP-in-a-box systems. They are closed systems, fluids can be processed and manipulated, and sensors integrated for real-time detection of process variables. Fabricated from polymers, they can be made disposable, i.e. single-use. Furthermore, microfluidics offers exquisite spatiotemporal control over the cellular microenvironment, promising both reproducibility and control of outcomes. In this chapter, we consider the challenges in cell manufacturing, highlight recent advances of microfluidic devices for each of the main process steps, and summarize our findings on the current state of the art. As microfluidic cell culture devices have been reported for both adherent and suspension cell cultures, we report on devices for the key process steps, or unit operations, of both stem cell therapies and cell-based immunotherapies.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hirsch T, Rothoeft T, Teig N et al (2017) Regeneration of the entire human epidermis using transgenic stem cells. Nature 551(7680):327–332. https://doi.org/10.1038/nature24487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shortt AJ, Tuft SJ, Daniels JT (2011) Corneal stem cells in the eye clinic. Br Med Bull 100(1):209–225. https://doi.org/10.1093/bmb/ldr041

    Article  PubMed  Google Scholar 

  3. Limb GA, Daniels JT (2008) Ocular regeneration by stem cells: present status and future prospects. Br Med Bull 85(1):47–61. https://doi.org/10.1093/bmb/ldn008

    Article  PubMed  Google Scholar 

  4. Chari S, Nguyen A, Saxe J (2018) Stem cells in the clinic. Cell Stem Cell 22(6):781–782. https://doi.org/10.1016/j.stem.2018.05.017

    Article  CAS  PubMed  Google Scholar 

  5. Mock U, Nickolay L, Weng P et al (2019) Automated manufacturing of CAR-T cells for adoptive immunotherapy using CliniMACS prodigy. J Chem Inf Model 53(9):1689–1699

    Google Scholar 

  6. Wang X, Rivière I (2016) Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics 3:16015. https://doi.org/10.1038/mto.2016.15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Levine BL, Miskin J, Wonnacott K, Keir C (2017) Global manufacturing of CAR T cell therapy. Mol Ther Methods Clin Dev 4:92–101. https://doi.org/10.1016/j.omtm.2016.12.006

    Article  CAS  PubMed  Google Scholar 

  8. Vormittag P, Gunn R, Ghorashian S, Veraitch FS (2018) A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol 53:164–181. https://doi.org/10.1016/j.copbio.2018.01.025

    Article  CAS  PubMed  Google Scholar 

  9. Hirschi KK, Li S, Roy K (2014) Induced pluripotent stem cells for regenerative medicine. Annu Rev Biomed Eng 16:277–294. https://doi.org/10.1146/annurev-bioeng-071813-105108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yamanaka S (2020) Pluripotent stem cell-based cell therapy – promise and challenges. Cell Stem Cell 27(4):523–531. https://doi.org/10.1016/j.stem.2020.09.014

    Article  CAS  PubMed  Google Scholar 

  11. Veraitch FS, Scott R, Wong JW, Lye GJ, Mason C (2008) The impact of manual processing on the expansion and directed differentiation of embryonic stem cells. Biotechnol Bioeng 99(5):1216–1229. https://doi.org/10.1002/bit.21673

    Article  CAS  PubMed  Google Scholar 

  12. Frank ND, Jones ME, Vang B, Coeshott C (2019) Evaluation of reagents used to coat the hollow-fiber bioreactor membrane of the quantum® cell expansion system for the culture of human mesenchymal stem cells. Mater Sci Eng C 96:77–85. https://doi.org/10.1016/j.msec.2018.10.081

    Article  CAS  Google Scholar 

  13. O’Hanlon CF, Fedczyna T, Eaker S, Shingleton WD, Helfer BM (2017) Integrating a 19F MRI tracer agent into the clinical scale manufacturing of a T-cell immunotherapy. Contrast Media Mol Imaging 2017. https://doi.org/10.1155/2017/9548478

  14. Radek C, Bernadin O, Drechsel K et al (2019) Vectofusin-1 improves transduction of primary human cells with diverse retroviral and lentiviral pseudotypes, enabling robust, automated closed-system manufacturing. Hum Gene Ther 30(12):1477–1493. https://doi.org/10.1089/hum.2019.157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Roberts I, Baila S, Rice RB et al (2012) Scale-up of human embryonic stem cell culture using a hollow fibre bioreactor. Biotechnol Lett 34(12):2307–2315. https://doi.org/10.1007/s10529-012-1033-1

    Article  CAS  PubMed  Google Scholar 

  16. Hanley PJ, Mei Z, Durett AG et al (2014) Efficient manufacturing of therapeutic mesenchymal stromal cells with the use of the quantum cell expansion system. Cytotherapy 16(8):1048–1058. https://doi.org/10.1016/j.jcyt.2014.01.417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nankervis B, Jones M, Vang B, Brent Rice R, Coeshott C, Beltzer J (2018) Optimizing T cell expansion in a hollow-fiber bioreactor. Curr Stem Cell Rep 4(1):46–51. https://doi.org/10.1007/s40778-018-0116-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xuri Cell Expansion System W25. Cytiva, formerly GE healthcare life sciences. https://www.cytivalifesciences.com/en/us/shop/cell-therapy/systems/xuri-cell-expansion-system-w25-p-06192. Accessed 29 Mar 2021

  19. Smith TA (2020) CAR-T cell expansion in a Xuri cell expansion system W25. In: Swiech K, Malmegrim KCR, Picanço-Castro V (eds) Chimeric antigen receptor T cells: development and production. Springer, New York, pp 151–163. https://doi.org/10.1007/978-1-0716-0146-4_11

    Chapter  Google Scholar 

  20. CliniMACS Prodigy | Cell manufacturing platform | Products | Miltenyi Biotec | USA. https://www.miltenyibiotec.com/US-en/products/cell-manufacturing-platform/clinimacs-prodigy.html. Accessed 29 Mar 2021

  21. Aglaris Facer 1.0 Cell culture platform – Aglaris. http://aglaris.co.uk/aglaris-facer-1-0-bioreactor/. Accessed 29 Mar 2021

  22. Cocoon® Platform | Lonza. https://pharma.lonza.com/technologies-products/cocoon-platform. Accessed 29 Mar 2021

  23. Leong W, Nankervis B, Beltzer J (2018) Automation: what will the cell therapy laboratory of the future look like? Cell Gene Ther Insights 4(9):679–694. https://doi.org/10.18609/cgti.2018.067

    Article  Google Scholar 

  24. Murthy SK (2014) Perspective on micro fl uidic cell separation: a solved problem? Anal Chem 86(23):11481–11488

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kim B, Kim KH, Chang Y, Shin S, Shin EC, Choi S (2019) One-step microfluidic purification of white blood cells from whole blood for immunophenotyping. Anal Chem 91(20):13230–13236. https://doi.org/10.1021/acs.analchem.9b03673

    Article  CAS  PubMed  Google Scholar 

  26. Chiu PL, Chang CH, Lin YL, Tsou PH, Li BR (2019) Rapid and safe isolation of human peripheral blood B and T lymphocytes through spiral microfluidic channels. Sci Rep 9(1):1–10. https://doi.org/10.1038/s41598-019-44677-3

    Article  CAS  Google Scholar 

  27. Nathamgari SSP, Dong B, Zhou F et al (2015) Isolating single cells in a neurosphere assay using inertial microfluidics. Lab Chip 15(24):4591–4597. https://doi.org/10.1039/c5lc00805k

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Di Carlo D (2009) Inertial microfluidics. Lab Chip 9(21):3038–3046. https://doi.org/10.1039/b912547g

    Article  CAS  PubMed  Google Scholar 

  29. Herrmann N, Neubauer P, Birkholz M (2019) Spiral microfluidic devices for cell separation and sorting in bioprocesses. Biomicrofluidics 13(6):061501. https://doi.org/10.1063/1.5125264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Acevedo JP, Angelopoulos I, van Noort D, Khoury M (2018) Microtechnology applied to stem cells research and development. Regen Med 13(2):233–248. https://doi.org/10.2217/rme-2017-0123

    Article  CAS  PubMed  Google Scholar 

  31. Ringwelski B, Jayasooriya V, Nawarathna D (2020) Dielectrophoretic high-purity isolation of primary T-cells in samples contaminated with leukemia cells, for biomanufacturing of therapeutic CAR T-cells. J Phys D Appl Phys 54(6). https://doi.org/10.1088/1361-6463/abc2f3

  32. Wang Z, Sargent EH, Kelley SO (2021) Ultrasensitive detection and depletion of rare leukemic B cells in T cell populations via Immunomagnetic cell ranking. Anal Chem 93(4):2327–2335. https://doi.org/10.1021/acs.analchem.0c04202

    Article  CAS  PubMed  Google Scholar 

  33. Seah YFS, Hu H, Merten CA (2018) Microfluidic single-cell technology in immunology and antibody screening. Mol Aspects Med 59:47–61. https://doi.org/10.1016/j.mam.2017.09.004

    Article  CAS  PubMed  Google Scholar 

  34. Choi JR (2020) Advances in single cell technologies in immunology. Biotechniques 69(3):227–236. https://doi.org/10.2144/btn-2020-0047

    Article  CAS  Google Scholar 

  35. Sarkar S (2015) T cell dynamic activation and functional analysis in nanoliter droplet microarray. J Clin Cell Immunol 6(3):334. https://doi.org/10.4172/2155-9899.1000334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Segaliny AI, Li G, Kong L et al (2018) Functional TCR T cell screening using single-cell droplet microfluidics. Lab Chip 18(24):3733–3749. https://doi.org/10.1039/c8lc00818c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Desalvo A, Bateman F, James E, Morgan H, Elliott T (2020) Time-resolved microwell cell-pairing array reveals multiple T cell activation profiles. Lab Chip 20(20):3772–3783. https://doi.org/10.1039/d0lc00628a

    Article  CAS  PubMed  Google Scholar 

  38. Ide H, Espulgar WV, Saito M et al (2021) Profiling T cell interaction and activation through microfluidics-assisted serial encounter with APCs. Sens Actuators B 330:129306. https://doi.org/10.1016/j.snb.2020.129306

    Article  CAS  Google Scholar 

  39. Lissandrello CA, Santos JA, Hsi P et al (2020) High-throughput continuous-flow microfluidic electroporation of mRNA into primary human T cells for applications in cellular therapy manufacturing. Sci Rep 10(1):1–16. https://doi.org/10.1038/s41598-020-73755-0

    Article  CAS  Google Scholar 

  40. Moore N, Chevillet JR, Healey LJ et al (2019) A microfluidic device to enhance viral transduction efficiency during manufacture of engineered cellular therapies. Sci Rep 9(1):1–11. https://doi.org/10.1038/s41598-019-50981-9

    Article  CAS  Google Scholar 

  41. Luni C, Giulitti S, Serena E et al (2016) High-efficiency cellular reprogramming with microfluidics. Nat Methods 13(5):446–452. https://doi.org/10.1038/nmeth.3832

    Article  CAS  PubMed  Google Scholar 

  42. Raimes W, Rubi M, Super A, Marques MPC, Veraitch F, Szita N (2017) Transfection in perfused microfluidic cell culture devices: a case study. Process Biochem 59:297–302. https://doi.org/10.1016/j.procbio.2016.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kang W, Giraldo-Vela JP, Nathamgari SSP et al (2014) Microfluidic device for stem cell differentiation and localized electroporation of postmitotic neurons. Lab Chip 14(23):4486–4495. https://doi.org/10.1039/c4lc00721b

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. El-Ali J, Sorger PK, Jensen KF (2006) Cells on chips. Nature 442(7101):403–411. https://doi.org/10.1038/nature05063

    Article  CAS  PubMed  Google Scholar 

  45. Kim L, Toh YC, Voldman J, Yu H (2007) A practical guide to microfluidic perfusion culture of adherent mammalian cells. Lab Chip 7(6):681–694. https://doi.org/10.1039/b704602b

    Article  CAS  PubMed  Google Scholar 

  46. Young EWK, Beebe DJ (2010) Fundamentals of microfluidic cell culture in controlled microenvironments. Chem Soc Rev 39(3):1036–1048. https://doi.org/10.1039/b909900j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Halldorsson S, Lucumi E, Gómez-Sjöberg R, Fleming RMT (2015) Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices. Biosens Bioelectron 63:218–231. https://doi.org/10.1016/j.bios.2014.07.029

    Article  CAS  PubMed  Google Scholar 

  48. Sackmann EK, Fulton AL, Beebe DJ (2014) The present and future role of microfluidics in biomedical research. Nature 507(7491):181–189. https://doi.org/10.1038/nature13118

    Article  CAS  PubMed  Google Scholar 

  49. Berthier E, Young EWK, Beebe D (2012) Engineers are from PDMS-land, biologists are from polystyrenia. Lab Chip 12(7):1224–1237. https://doi.org/10.1039/c2lc20982a

    Article  CAS  PubMed  Google Scholar 

  50. Mehling M, Tay S (2014) Microfluidic cell culture. Curr Opin Biotechnol 25:95–102. https://doi.org/10.1016/j.copbio.2013.10.005

    Article  CAS  PubMed  Google Scholar 

  51. Sibbitts J, Sellens KA, Jia S, Klasner SA, Culbertson CT (2017) Cellular analysis using microfluidics. Anal Chem 89:711–719. https://doi.org/10.1021/acs.analchem.7b04519

    Article  CAS  Google Scholar 

  52. García Alonso D, Yu M, Qu H, Ma L, Shen F (2019) Advances in microfluidics-based technologies for single cell culture. Adv Biosyst 3(11):1900003. https://doi.org/10.1002/adbi.201900003

    Article  Google Scholar 

  53. Gupta N, Liu JR, Patel B, Solomon DE, Vaidya B, Gupta V (2016) Microfluidics-based 3D cell culture models: utility in novel drug discovery and delivery research. Bioeng Transl Med 1(1):63–81. https://doi.org/10.1002/btm2.10013

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cochrane A, Albers HJ, Passier R et al (2019) Advanced in vitro models of vascular biology: human induced pluripotent stem cells and organ-on-chip technology. Adv Drug Deliv Rev 140:68–77. https://doi.org/10.1016/j.addr.2018.06.007

    Article  CAS  PubMed  Google Scholar 

  55. Grün C, Altmann B, Gottwald E (2020) Advanced 3D cell culture techniques in micro-bioreactors, part I: a systematic analysis of the literature published between 2000 and 2020. Processes 8(12):1656. https://doi.org/10.3390/pr8121656

    Article  CAS  Google Scholar 

  56. Altmann B, Grün C, Nies C, Gottwald E (2020) Advanced 3D cell culture techniques in micro-bioreactors, part II: systems and applications. https://doi.org/10.3390/pr9010021

  57. Lesher-Perez SC, Frampton JP, Takayama S (2013) Microfluidic systems: a new toolbox for pluripotent stem cells. Biotechnol J 8(2):180–191. https://doi.org/10.1002/biot.201200206

    Article  CAS  PubMed  Google Scholar 

  58. Titmarsh DM, Chen H, Glass NR, Cooper-White JJ (2014) Concise review: microfluidic technology platforms: poised to accelerate development and translation of stem cell-derived therapies. Stem Cells Transl Med 3(1):81–90. https://doi.org/10.5966/sctm.2013-0118

    Article  PubMed  Google Scholar 

  59. Zhang J, Wei X, Zeng R, Xu F, Li XJ (2017) Stem cell culture and differentiation in microfluidic devices toward organ-on-a-chip. Future Sci OA 3:FSO187. https://doi.org/10.4155/fsoa-2016-0091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Morsink M, Willemen N, Leijten J, Bansal R, Shin S (2020) Immune organs and immune cells on a chip: an overview of biomedical applications. Micromachines 11(9):849. https://doi.org/10.3390/mi11090849

    Article  PubMed Central  Google Scholar 

  61. Varma S, Voldman J (2018) Caring for cells in microsystems: principles and practices of cell-safe device design and operation. Lab Chip 18(22):3333–3352. https://doi.org/10.1039/C8LC00746B

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Coluccio ML, Perozziello G, Malara N et al (2019) Microfluidic platforms for cell cultures and investigations. Microelectron Eng 208:14–28. https://doi.org/10.1016/j.mee.2019.01.004

    Article  CAS  Google Scholar 

  63. Kirouac DC, Zandstra PW (2008) The systematic production of cells for cell therapies. Cell Stem Cell 3(4):369–381. https://doi.org/10.1016/j.stem.2008.09.001

    Article  CAS  PubMed  Google Scholar 

  64. Yoshimitsu R, Hattori K, Sugiura S et al (2014) Microfluidic perfusion culture of human induced pluripotent stem cells under fully defined culture conditions. Biotechnol Bioeng 111(5):937–947. https://doi.org/10.1002/bit.25150

    Article  CAS  PubMed  Google Scholar 

  65. Korin N, Bransky A, Dinnar U, Levenberg S (2009) Periodic “flow-stop” perfusion microchannel bioreactors for mammalian and human embryonic stem cell long-term culture. Biomed Microdevices 11:87–94. https://doi.org/10.1007/s10544-008-9212-5

    Article  PubMed  Google Scholar 

  66. Titmarsh D, Hidalgo A, Turner J, Wolvetang E, Cooper-White J (2011) Optimization of flowrate for expansion of human embryonic stem cells in perfusion microbioreactors. Biotechnol Bioeng 108(12):2894–2904. https://doi.org/10.1002/bit.23260

    Article  CAS  PubMed  Google Scholar 

  67. Super A, Jaccard N, Marques MPC et al (2016) Real-time monitoring of specific oxygen uptake rates of embryonic stem cells in a microfluidic cell culture device. Biotechnol J 11(9):1179–1189. https://doi.org/10.1002/biot.201500479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Reichen M, Veraitch FS, Szita N (2013) Development of a multiplexed microfluidic platform for the automated cultivation of embryonic stem cells. J Lab Autom 18(6):519–529. https://doi.org/10.1177/2211068213499917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Reichen M, Macown RJ, Jaccard N et al (2012) Microfabricated modular scale-down device for regenerative medicine process development. PLoS One 7(12):e52246. https://doi.org/10.1371/journal.pone.0052246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jaccard N, Szita N, Griffin LD (2017) Segmentation of phase contrast microscopy images based on multi-scale local basic image features histograms. Comput Methods Biomech Biomed Eng Imaging Vis 5(5):359–367. https://doi.org/10.1080/21681163.2015.1016243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gruber P, Marques MPC, Szita N, Mayr T (2017) Integration and application of optical chemical sensors in microbioreactors. Lab Chip 17(16):2693–2712. https://doi.org/10.1039/c7lc00538e

    Article  CAS  PubMed  Google Scholar 

  72. Zirath H, Rothbauer M, Spitz S et al (2018) Every breath you take: non-invasive real-time oxygen biosensing in two- and three-dimensional microfluidic cell models. Front Physiol 9:815. https://doi.org/10.3389/fphys.2018.00815

    Article  PubMed  PubMed Central  Google Scholar 

  73. Yin L, Wu Y, Yang Z et al (2018) Lab on a chip microfluidic label-free selection of mesenchymal stem cell subpopulation during culture expansion extends the chondrogenic potential in vitro. Lab Chip 18:878. https://doi.org/10.1039/c7lc01005b

    Article  CAS  PubMed  Google Scholar 

  74. Strachan BC, Xia HUI, Vörös E, Gifford SC, Shevkoplyas SS (2019) Improved expansion of T cells in culture when isolated with an equipment-free, high-throughput, flow-through microfluidic module versus traditional density gradient centrifugation. Cytotherapy 21(2):234–245. https://doi.org/10.1016/j.jcyt.2018.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hashemzadeh H, Allahverdi A, Sedghi M et al (2020) PDMS Nano-modified scaffolds for improvement of stem cells proliferation and differentiation in microfluidic platform. Nanomaterials (Basel) 10(4):668. https://doi.org/10.3390/nano10040668

    Article  CAS  Google Scholar 

  76. Ye F, Yan Z, Zhang H, Chang H, Neuzil P (2020) Microfabricated stem cell targeted differentiation systems. Trends Anal Chem 126:115858. https://doi.org/10.1016/j.trac.2020.115858

    Article  CAS  Google Scholar 

  77. Jang S, Collin de l’Hortet A, Soto-Gutierrez A (2019) Induced pluripotent stem cell–derived endothelial cells: overview, current advances, applications, and future directions. Am J Pathol 189(3):502–512. https://doi.org/10.1016/j.ajpath.2018.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Afflerbach AK, Kiri MD, Detinis T, Maoz BM (2020) Mesenchymal stem cells as a promising cell source for integration in novel in vitro models. Biomol Ther 10(9):1–30. https://doi.org/10.3390/biom10091306

    Article  CAS  Google Scholar 

  79. Dame K, Ribeiro AJS (2021) Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects. Exp Biol Med 246(3):317–331. https://doi.org/10.1177/1535370220959598

    Article  CAS  Google Scholar 

  80. Jang J, Yoo J-E, Lee J-A et al (2012) Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery. Exp Mol Med 44(3):202–213. https://doi.org/10.3858/emm.2012.44.3.015

    Article  CAS  PubMed  Google Scholar 

  81. Moreno EL, Hachi S, Hemmer K et al (2015) Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture. Lab Chip 15(11):2419–2428. https://doi.org/10.1039/c5lc00180c

    Article  CAS  PubMed  Google Scholar 

  82. Kane KIW, Moreno EL, Hachi S et al (2019) Automated microfluidic cell culture of stem cell derived dopaminergic neurons. Sci Rep 9(1):1–12. https://doi.org/10.1038/s41598-018-34828-3

    Article  CAS  Google Scholar 

  83. Abdolvand N, Tostoes R, Raimes W, Kumar V, Szita N, Veraitch F (2019) Long-term retinal differentiation of human induced pluripotent stem cells in a continuously perfused microfluidic culture device. Biotechnol J 14(3):1800323. https://doi.org/10.1002/biot.201800323

    Article  CAS  Google Scholar 

  84. Kim HW, Lim J, Rhie JW, Kim DS (2017) Investigation of effective shear stress on endothelial differentiation of human adipose-derived stem cells with microfluidic screening device. Microelectron Eng 174:24–27. https://doi.org/10.1016/j.mee.2016.12.022

    Article  CAS  Google Scholar 

  85. Pavesi A, Adriani G, Rasponi M, Zervantonakis IK, Fiore GB, Kamm RD (2015) Controlled electromechanical cell stimulation on-a-chip. Sci Rep 5:11800. https://doi.org/10.1038/srep11800

    Article  PubMed  PubMed Central  Google Scholar 

  86. Kim KM, Choi YJ, Hwang J-HJH et al (2014) Shear stress induced by an interstitial level of slow flow increases the osteogenic differentiation of mesenchymal stem cells through TAZ activation. PLoS One 9(3):92427. https://doi.org/10.1371/journal.pone.0092427

    Article  CAS  Google Scholar 

  87. Wang B, Jedlicka S, Cheng X (2014) Maintenance and neuronal cell differentiation of neural stem cells C17.2 correlated to medium availability sets design criteria in microfluidic systems. PLoS One 9(10):1–15. https://doi.org/10.1371/journal.pone.0109815

    Article  CAS  Google Scholar 

  88. Wu HW, Lin CC, Hwang SM, Chang YJ, Bin LG (2011) A microfluidic device for chemical and mechanical stimulation of mesenchymal stem cells. Microfluid Nanofluid 11(5):545–556. https://doi.org/10.1007/s10404-011-0820-7

    Article  CAS  Google Scholar 

  89. Tenstad E, Tourovskaia A, Folch A, Myklebost O, Rian E (2010) Extensive adipogenic and osteogenic differentiation of patterned human mesenchymal stem cells in a microfluidic device. Lab Chip 10(11):1401–1409. https://doi.org/10.1039/b926738g

    Article  CAS  Google Scholar 

  90. Vishnu VP, Lenferink A, Van Manen HJ, Subramaniam V, Van Blitterswijk CA, Otto C (2010) Microbioreactors for raman microscopy of stromal cell differentiation. Anal Chem 82(5):1844–1850. https://doi.org/10.1021/ac902515c

    Article  CAS  Google Scholar 

  91. Ong LJY, Chong LH, Jin L et al (2017) A pump-free microfluidic 3D perfusion platform for the efficient differentiation of human hepatocyte-like cells. Biotechnol Bioeng 114(10):2360–2370. https://doi.org/10.1002/bit.26341

    Article  CAS  PubMed  Google Scholar 

  92. Kilic O, Pamies D, Lavell E et al (2016) Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis. Lab Chip 16(21):4152–4162. https://doi.org/10.1039/c6lc00946h

    Article  CAS  PubMed  Google Scholar 

  93. Kleine-Brüggeney H, van Vliet LD, Mulas C et al (2019) Long-term perfusion culture of monoclonal embryonic stem cells in 3D hydrogel beads for continuous optical analysis of differentiation. Small 15(5):1–11. https://doi.org/10.1002/smll.201804576

    Article  CAS  Google Scholar 

  94. Kim C, Bang JH, Kim YE, Lee JH, Kang JY (2012) Stable hydrodynamic trapping of hydrogel beads for on-chip differentiation analysis of encapsulated stem cells. Sens Actuators B 166–167:859–869. https://doi.org/10.1016/j.snb.2012.02.008

    Article  CAS  Google Scholar 

  95. Guzzi F, Candeloro P, Coluccio ML et al (2020) A disposable passive microfluidic device for cell culturing. Biosensors 10(3):1–14. https://doi.org/10.3390/bios10030018

    Article  CAS  Google Scholar 

  96. Adriani G, Pavesi A, Tan AT, Bertoletti A, Thiery JP, Kamm RD (2016) Microfluidic models for adoptive cell-mediated cancer immunotherapies. Drug Discov Today 21(9):1472–1478. https://doi.org/10.1016/j.drudis.2016.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ando Y, Siegler EL, Ta HP et al (2019) Evaluating CAR-T cell therapy in a hypoxic 3D tumor model. Adv Healthc Mater 8(5):1–15. https://doi.org/10.1002/adhm.201900001

    Article  CAS  Google Scholar 

  98. Xu R, Zhou X, Wang S, Trinkle C (2021) Tumor organoid models in precision medicine and investigating cancer-stromal interactions. Pharmacol Ther 218:107668. https://doi.org/10.1016/j.pharmthera.2020.107668

    Article  CAS  PubMed  Google Scholar 

  99. Tanyeri M, Tay S (2018) Viable cell culture in PDMS-based microfluidic devices. Methods Cell Biol 148:3–33. https://doi.org/10.1016/bs.mcb.2018.09.007

    Article  CAS  PubMed  Google Scholar 

  100. Regehr K, Domenech M, Koepsel J et al (2009) Biological implications of polydimethylsiloxane-based microfluidic cell culture. Lab Chip 9(15):2132–2139. https://doi.org/10.1039/b903043c.Biological

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Renckens TJA, Janeliunas D, van Vliet H, van Esch JH, Mul G, Kreutzer MT (2011) Micromolding of solvent resistant microfluidic devices. Lab Chip 11(12):2035–2038. https://doi.org/10.1039/c0lc00550a

    Article  CAS  PubMed  Google Scholar 

  102. Zhou J, Ellis AV, Voelcker NH (2010) Recent developments in PDMS surface modification for microfluidic devices. Electrophoresis 31(1):2–16. https://doi.org/10.1002/elps.200900475

    Article  CAS  PubMed  Google Scholar 

  103. Kamei KI, Guo S, Yu ZTF et al (2009) An integrated microfluidic culture device for quantitative analysis of human embryonic stem cells. Lab Chip 9(4):555–563. https://doi.org/10.1039/b809105f

    Article  CAS  PubMed  Google Scholar 

  104. Wolf MP, Salieb-Beugelaar GB, Hunziker P (2018) PDMS with designer functionalities – properties, modifications strategies, and applications. Prog Polym Sci 83:97–134. https://doi.org/10.1016/j.progpolymsci.2018.06.001

    Article  CAS  Google Scholar 

  105. Chuah YJ, Koh YT, Lim K, Menon NV, Wu Y, Kang Y (2015) Simple surface engineering of polydimethylsiloxane with polydopamine for stabilized mesenchymal stem cell adhesion and multipotency. Sci Rep 5:1–12. https://doi.org/10.1038/srep18162

    Article  CAS  Google Scholar 

  106. Chuah YJ, Kuddannaya S, Lee MHA, Zhang Y, Kang Y (2015) The effects of poly(dimethylsiloxane) surface silanization on the mesenchymal stem cell fate. Biomater Sci 3(2):383–390. https://doi.org/10.1039/c4bm00268g

    Article  CAS  PubMed  Google Scholar 

  107. Liu W, Sun M, Han K, Hu R, Liu D, Wang J (2020) Comprehensive evaluation of stable neuronal cell adhesion and culture on one-step modified polydimethylsiloxane using functionalized Pluronic. ACS Omega 5(50):32753–32760. https://doi.org/10.1021/acsomega.0c05190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Villa-Diaz LG, Torisawa YS, Uchida T et al (2009) Microfluidic culture of single human embryonic stem cell colonies. Lab Chip 9(12):1749–1755. https://doi.org/10.1039/b820380f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Blagovic K, Kim LY, Voldman J (2011) Microfluidic perfusion for regulating diffusible signaling in stem cells. PLoS One 6(8). https://doi.org/10.1371/journal.pone.0022892

  110. Siller IG, Enders A, Steinwedel T et al (2019) Real-time live-cell imaging technology enables high-throughput screening to verify in vitro biocompatibility of 3D printed materials. Materials (Basel) 12(13):1–17. https://doi.org/10.3390/ma12132125

    Article  CAS  Google Scholar 

  111. Siller IG, Epping NM, Lavrentieva A, Scheper T, Bahnemann J (2020) Customizable 3D-printed (Co-)cultivation systems for in vitro study of angiogenesis. Materials (Basel) 13(19):1–17. https://doi.org/10.3390/ma13194290

    Article  CAS  Google Scholar 

  112. Ong LJY, Islam A, Dasgupta R, Iyer NG, Leo HL, Toh YC (2017) A 3D printed microfluidic perfusion device for multicellular spheroid cultures. Biofabrication 9(4). https://doi.org/10.1088/1758-5090/aa8858

  113. Beckwith AL, Borenstein JT, Velasquez-Garcia LF (2018) Monolithic, 3D-printed microfluidic platform for recapitulation of dynamic tumor microenvironments. J Microelectromech Syst 27(6):1009–1022. https://doi.org/10.1109/JMEMS.2018.2869327

    Article  CAS  Google Scholar 

  114. Titmarsh DM, Glass NR, Mills RJ et al (2016) Induction of human iPSC-derived cardiomyocyte proliferation revealed by combinatorial screening in high density microbioreactor arrays. Sci Rep 6:1–15. https://doi.org/10.1038/srep24637

    Article  CAS  Google Scholar 

  115. Cambier T, Honegger T, Vanneaux V et al (2015) Design of a 2D no-flow chamber to monitor hematopoietic stem cells. Lab Chip 15(1):77–85. https://doi.org/10.1039/c4lc00807c

    Article  CAS  PubMed  Google Scholar 

  116. Occhetta P, Centola M, Tonnarelli B, Redaelli A, Martin I, Rasponi M (2015) High-throughput microfluidic platform for 3D cultures of mesenchymal stem cells, towards engineering developmental processes. Sci Rep 5:1–12. https://doi.org/10.1038/srep10288

    Article  CAS  Google Scholar 

  117. Bhattacharjee N, Folch A (2017) Large-scale microfluidic gradient arrays reveal axon guidance behaviors in hippocampal neurons. Microsyst Nanoeng 3(1). https://doi.org/10.1038/micronano.2017.3

  118. Skafte-Pedersen P, Hemmingsen M, Sabourin D, Blaga FS, Bruus H, Dufva M (2012) A self-contained, programmable microfluidic cell culture system with real-time microscopy access. Biomed Microdevices 14(2):385–399. https://doi.org/10.1007/s10544-011-9615-6

    Article  CAS  PubMed  Google Scholar 

  119. Jaccard N, Macown RJ, Super A, Griffin LD, Veraitch FS, Szita N (2014) Automated and online characterization of adherent cell culture growth in a microfabricated bioreactor. J Lab Autom 19(5):437–443. https://doi.org/10.1177/2211068214529288

    Article  PubMed  PubMed Central  Google Scholar 

  120. Macown RJ, Veraitch FS, Szita N (2014) Robust, microfabricated culture devices with improved control over the soluble microenvironment for the culture of embryonic stem cells. Biotechnol J 9(6):805–813. https://doi.org/10.1002/biot.201300245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the excellent service of the Servier Medical Art (SMART) website https://smart.servier.com/ providing icons and cartoons free-of-charge that we used for our illustrations, including the graphical abstract. UCL Biochemical Engineering hosts the Future Targeted Healthcare Manufacturing Hub in collaboration with UK universities and with funding from the UK Engineering & Physical Sciences Research Council (EPSRC, EP/P006485/1) and a consortium of industrial users and sector organisations. The authors also gratefully acknowledge the Engineering and Physical Sciences Research Council (EPSRC, EP/I005471/1, EP/L01520X/1, EP/S01778X/1, EP/S021868/1) and the Biotechnology and Biological Sciences Research Council (BBSRC, BB/L000997/1) for further funding.

Author information

Authors and Affiliations

  1. Biochemical Engineering Department, University College London (UCL), London, UK

    Jorge Aranda Hernandez & Nicolas Szita

  2. Institute of Technical Chemistry, Leibniz University Hannover, Hannover, Germany

    Christopher Heuer & Janina Bahnemann

Authors
  1. Jorge Aranda Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Heuer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Janina Bahnemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicolas Szita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicolas Szita .

Editor information

Editors and Affiliations

  1. Institute of Physics, University of Augsburg, Augsburg, Germany

    Janina Bahnemann

  2. Multiscale Bioengineering, Faculty of Technology, Bielefeld University, Bielefeld, Germany

    Alexander Grünberger

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Aranda Hernandez, J., Heuer, C., Bahnemann, J., Szita, N. (2021). Microfluidic Devices as Process Development Tools for Cellular Therapy Manufacturing. In: Bahnemann, J., Grünberger, A. (eds) Microfluidics in Biotechnology. Advances in Biochemical Engineering/Biotechnology, vol 179. Springer, Cham. https://doi.org/10.1007/10_2021_169

Download citation

Publish with us

Policies and ethics

Search

Navigation