Bioreactor Systems in Regenerative Medicine

  • Ivan MartinEmail author
  • Stefania A. Riboldi
  • David Wendt
Conference paper
Part of the NATO Science for Peace and Security Series A: Chemistry and Biology book series (NAPSA)


In this chapter, the functions and potential applicability of bioreactors from a technical, scientific and clinical perspective will be reviewed in the context of tissue engineering and regenerative medicine. In particular, examples will be given to illustrate the role of bioreactors in (a) establishing and maintaining 3D cell cultures, (b) standardizing physicochemical culture parameters, (c) physically conditioning engineered grafts, (d) predicting mechanical functionality of constructs to be implanted, (e) automating conventional tissue culture processes, (f) streamlining tissue manufacturing strategies. The critical role of bioreactors to make tissue engineered products clinically accessible, safe and commercially competitive will finally be discussed.


Tissue engineering Cell-based therapy Graft manufacturing Physical conditioning Perfusion flow 


  1. Altman GH, Lu HH, Horan RL et al (2002) Advanced bioreactor with controlled application of multi-dimensional strain for tissue engineering. J Biomech Eng 124:742–749CrossRefGoogle Scholar
  2. Bancroft GN, Sikavitsas VI, van den DJ et al (2002) Fluid flow increases mineralized matrix deposition in 3D perfusion culture of marrow stromal osteoblasts in a dose-dependent manner. Proc Natl Acad Sci USA 99:12600–12605CrossRefGoogle Scholar
  3. Braccini A, Wendt D, Jaquiery C et al (2005) Three-dimensional perfusion culture of human bone marrow cells and generation of osteoinductive grafts. Stem Cells 23:1066–1072CrossRefGoogle Scholar
  4. Brosenitsch TA, Katz DM (2001) Physiological patterns of electrical stimulation can induce neuronal gene expression by activating N-type calcium channels. J Neurosci 21:2571–2579Google Scholar
  5. Bueno EM, Laevsky G, Barabino GA (2007) Enhancing cell seeding of scaffolds in tissue engineering through manipulation of hydrodynamic parameters. J Biotechnol 129:516–531CrossRefGoogle Scholar
  6. Candrian C, Vonwil D, Barbero A et al (2007) Engineered cartilage generated by nasal chondrocytes is responsive to physical forces resembling joint loading. Arthritis Rheum 58:197–208CrossRefGoogle Scholar
  7. Chen JP, Lin CT (2006) Dynamic seeding and perfusion culture of hepatocytes with galactosylated vegetable sponge in packed-bed bioreactor. J Biosci Bioeng 102:41–45CrossRefGoogle Scholar
  8. Cioffi M, Boschetti F, Raimondi MT et al (2006) Modeling evaluation of the fluid-dynamic microenvironment in tissue-engineered constructs: a micro-CT based model. Biotechnol Bioeng 93:500–510CrossRefGoogle Scholar
  9. Davisson T, Kunig S, Chen A et al (2002a) Static and dynamic compression modulate matrix metabolism in tissue engineered cartilage. J Orthop Res 20:842–848CrossRefGoogle Scholar
  10. Davisson T, Sah RL, Ratcliffe A (2002b) Perfusion increases cell content and matrix synthesis in chondrocyte three-dimensional cultures. Tissue Eng 8:807–816CrossRefGoogle Scholar
  11. Demarteau O, Wendt D, Braccini A et al (2003) Dynamic compression of cartilage constructs engineered from expanded human articular chondrocytes. Biochem Biophys Res Commun 310:580–588CrossRefGoogle Scholar
  12. Dvir T, Benishti N, Shachar M et al (2006) A novel perfusion bioreactor providing a homogenous milieu for tissue regeneration. Tissue Eng 12:2843–2852CrossRefGoogle Scholar
  13. Fassnacht D, Portner R (1999) Experimental and theoretical considerations on oxygen supply for animal cell growth in fixed-bed reactors. J Biotechnol 72:169–184CrossRefGoogle Scholar
  14. Fink C, Ergun S, Kralisch D et al (2000) Chronic stretch of engineered heart tissue induces hypertrophy and functional improvement. FASEB J 14:669–679Google Scholar
  15. Flanagan TC, Cornelissen C, Koch S et al (2007) The in vitro development of autologous fibrin-based tissue-engineered heart valves through optimised dynamic conditioning. Biomaterials 28:3388–3397CrossRefGoogle Scholar
  16. Freed LE, Vunjak-Novakovic G (1997) Microgravity tissue engineering. In Vitro Cell Dev Biol Anim 33:381–385CrossRefGoogle Scholar
  17. Galbusera F, Cioffi M, Raimondi MT et al (2007) Computational modeling of combined cell population dynamics and oxygen transport in engineered tissue subject to interstitial perfusion. Comput Methods Biomech Biomed Eng 10:279–287CrossRefGoogle Scholar
  18. Grad S, Lee CR, Gorna K et al (2005) Surface motion upregulates superficial zone protein and hyaluronan production in chondrocyte-seeded three-dimensional scaffolds. Tissue Eng 11:249–256CrossRefGoogle Scholar
  19. Hahn MS, McHale MK, Wang E et al (2007) Physiologic pulsatile flow bioreactor conditioning of poly(ethylene glycol)-based tissue engineered vascular grafts. Ann Biomed Eng 35:190–200CrossRefGoogle Scholar
  20. Hoerstrup SP, Zund G, Sodian R et al (2001) Tissue engineering of small caliber vascular grafts. Eur J Cardiothorac Surg 20:164–169CrossRefGoogle Scholar
  21. Janssen FW, Hofland I, van OA et al (2006a) Online measurement of oxygen consumption by goat bone marrow stromal cells in a combined cell-seeding and proliferation perfusion bioreactor. J Biomed Mater Res A 79:338–348Google Scholar
  22. Janssen FW, Oostra J, Oorschot A et al (2006b) A perfusion bioreactor system capable of producing clinically relevant volumes of tissue-engineered bone: in vivo bone formation showing proof of concept. Biomaterials 27:315–323CrossRefGoogle Scholar
  23. Kafienah W, Jakob M, Demarteau O et al (2002) Three-dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes. Tissue Eng 8:817–826CrossRefGoogle Scholar
  24. Karim N, Golz K, Bader A (2006) The cardiovascular tissue-reactor: a novel device for the engineering of heart valves. Artif Organs 30:809–814CrossRefGoogle Scholar
  25. Kino-Oka M, Ogawa N, Umegaki R et al (2005) Bioreactor design for successive culture of anchorage-dependent cells operated in an automated manner. Tissue Eng 11:535–545CrossRefGoogle Scholar
  26. Kitagawa T, Yamaoka T, Iwase R et al (2006) Three-dimensional cell seeding and growth in radial-flow perfusion bioreactor for in vitro tissue reconstruction. Biotechnol Bioeng 93:947–954CrossRefGoogle Scholar
  27. Knoll A, Scherer T, Poggendorf I et al (2004) Flexible automation of cell culture and tissue engineering tasks. Biotechnol Prog 20:1825–1835CrossRefGoogle Scholar
  28. Li Y, Ma T, Kniss DA et al (2001) Effects of filtration seeding on cell density, spatial distribution, and proliferation in nonwoven fibrous matrices. Biotechnol Prog 17:935–944CrossRefGoogle Scholar
  29. Mantero S, Sadr N, Riboldi SA et al (2007) A new electro-mechanical bioreactor for soft tissue engineering. JABB 5:107–116Google Scholar
  30. Marston WA, Hanft J, Norwood P et al (2003) The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 26:1701–1705CrossRefGoogle Scholar
  31. Martin I, Wendt D, Heberer M (2004) The role of bioreactors in tissue engineering. Trends Biotechnol 22:80–86CrossRefGoogle Scholar
  32. Mason C, Hoare M (2006) Regenerative medicine bioprocessing: the need to learn from the experience of other fields. Regen Med 1:615–623CrossRefGoogle Scholar
  33. Mason C, Hoare M (2007) Regenerative medicine bioprocessing: building a conceptual framework based on early studies. Tissue Eng 13:301–311CrossRefGoogle Scholar
  34. Mauney JR, Sjostorm S, Blumberg J et al (2004) Mechanical stimulation promotes osteogenic differentiation of human bone marrow stromal cells on 3-D partially demineralized bone scaffolds in vitro. Calcif Tissue Int 74:458–468CrossRefGoogle Scholar
  35. Mayhew TA, Williams GR, Senica MA et al (1998) Validation of a quality assurance program for autologous cultured chondrocyte implantation. Tissue Eng 4:325–334CrossRefGoogle Scholar
  36. Mol A, Driessen NJ, Rutten MC et al (2005) Tissue engineering of human heart valve leaflets: a novel bioreactor for a strain-based conditioning approach. Ann Biomed Eng 33:1778–1788CrossRefGoogle Scholar
  37. Naughton GK (2002) From lab bench to market: critical issues in tissue engineering. Ann N Y Acad Sci 961:372–385CrossRefGoogle Scholar
  38. Niklason LE, Gao J, Abbott WM et al (1999) Functional arteries grown in vitro. Science 284:489–493CrossRefGoogle Scholar
  39. Pedrotty DM, Koh J, Davis BH et al (2005) Engineering skeletal myoblasts: roles of three-dimensional culture and electrical stimulation. Am J Physiol Heart Circ Physiol 288:H1620–H1626CrossRefGoogle Scholar
  40. Porter B, Zauel R, Stockman H et al (2005) 3-D computational modeling of media flow through scaffolds in a perfusion bioreactor. J Biomech 38:543–549CrossRefGoogle Scholar
  41. Powell CA, Smiley BL, Mills J et al (2002) Mechanical stimulation improves tissue-engineered human skeletal muscle. Am J Physiol Cell Physiol 283:C1557–C1565Google Scholar
  42. Prenosil JE, Kino-Oka M (1999) Computer controlled bioreactor for large-scale production of cultured skin grafts. Ann N Y Acad Sci 875:386–397CrossRefGoogle Scholar
  43. Radisic M, Euloth M, Yang L et al (2003) High-density seeding of myocyte cells for cardiac tissue engineering. Biotechnol Bioeng 82:403–414CrossRefGoogle Scholar
  44. Radisic M, Park H, Shing H et al (2004a) Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc Natl Acad Sci USA 101:18129–18134CrossRefGoogle Scholar
  45. Radisic M, Yang L, Boublik J et al (2004b) Medium perfusion enables engineering of compact and contractile cardiac tissue. Am J Physiol Heart Circ Physiol 286:H507–H516CrossRefGoogle Scholar
  46. Raimondi MT, Moretti M, Cioffi M et al (2006) The effect of hydrodynamic shear on 3D engineered chondrocyte systems subject to direct perfusion. Biorheology 43:215–222Google Scholar
  47. Scapinelli R, Aglietti P, Baldovin M et al (2002) Biologic resurfacing of the patella: current status. Clin Sports Med 21:547–573CrossRefGoogle Scholar
  48. Scherberich A, Galli R, Jaquiery C et al (2007) Three-dimensional perfusion culture of human adipose tissue-derived endothelial and osteoblastic progenitors generates osteogenic constructs with intrinsic vascularization capacity. Stem Cells 25:1823–1829CrossRefGoogle Scholar
  49. Shangkai C, Naohide T, Koji Y et al (2007) Transplantation of allogeneic chondrocytes cultured in fibroin sponge and stirring chamber to promote cartilage regeneration. Tissue Eng 13:483–492CrossRefGoogle Scholar
  50. Sikavitsas VI, Bancroft GN, Lemoine JJ et al (2005) Flow perfusion enhances the calcified matrix deposition of marrow stromal cells in biodegradable nonwoven fiber mesh scaffolds. Ann Biomed Eng 33:63–70CrossRefGoogle Scholar
  51. Sodian R, Lemke T, Fritsche C et al (2002) Tissue-engineering bioreactors: a new combined cell-seeding and perfusion system for vascular tissue engineering. Tissue Eng 8:863–870CrossRefGoogle Scholar
  52. Stevens MM, Marini RP, Schaefer D et al (2005) In vivo engineering of organs: the bone bioreactor. Proc Natl Acad Sci U S A 102:11450–11455CrossRefGoogle Scholar
  53. Sun T, Norton D, Haycock JW et al (2005) Development of a closed bioreactor system for culture of tissue-engineered skin at an air-liquid interface. Tissue Eng 11:1824–1831CrossRefGoogle Scholar
  54. Thompson CA, Colon-Hernandez P, Pomerantseva I et al (2002) A novel pulsatile, laminar flow bioreactor for the development of tissue-engineered vascular structures. Tissue Eng 8:1083–1088CrossRefGoogle Scholar
  55. Timmins NE, Scherberich A, Fruh JA et al (2007) Three-dimensional cell culture and tissue engineering in a T-CUP (tissue culture under perfusion). Tissue Eng 13:2021–2028CrossRefGoogle Scholar
  56. Vonwil D, Barbero A, Quinn T et al (2007) Expansion of adult human chondrocytes on an extendable surface: a strategy to reduce passageing-related dedifferentiation. Eur Cell Mater 13:17Google Scholar
  57. Vunjak-Novakovic G, Martin I, Obradovic B et al (1999) Bioreactor cultivation conditions modulate the composition and mechanical properties of tissue-engineered cartilage. J Orthop Res 17:130–138CrossRefGoogle Scholar
  58. Wendt D, Marsano A, Jakob M et al (2003) Oscillating perfusion of cell suspensions through three-dimensional scaffolds enhances cell seeding efficiency and uniformity. Biotechnol Bioeng 84:205–214CrossRefGoogle Scholar
  59. Wendt D, Stroebel S, Jakob M et al (2006) Uniform tissues engineered by seeding and culturing cells in 3D scaffolds under perfusion at defined oxygen tensions. Biorheology 43:481–488Google Scholar
  60. Wernike E, Li Z, Alini M et al (2007) Effect of reduced oxygen tension and long-term mechanical stimulation on chondrocyte-polymer constructs. Cell Tissue ResGoogle Scholar
  61. Yang J, Yamato M, Shimizu T et al (2007) Reconstruction of functional tissues with cell sheet engineering. Biomaterials 28:5033–5043CrossRefGoogle Scholar
  62. Zhao F, Ma T (2005) Perfusion bioreactor system for human mesenchymal stem cell tissue engineering: dynamic cell seeding and construct development. Biotechnol Bioeng 91:482–493CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Ivan Martin
    • 1
    Email author
  • Stefania A. Riboldi
    • 1
  • David Wendt
    • 1
  1. 1.Institute for Surgical Research and Hospital Management, Departments of Surgery and of BiomedicineUniversity Hospital BaselBaselSwitzerland

Personalised recommendations