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Microbeads and anchorage-dependent eukaryotic cells: The beginning of a new era in biotechnology

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Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 39/1))

Abstract

Modern methods for the mass cultivation of anchorage-dependent mammalian cells started with the advent of microcarrier technology. Largely for reasons pertaining to their mode of preparation and ease of cultivation, 150–230 Μm microbeads have been overwhelmingly adopted and the technology around them developed. To meet high biomass, macroporous microbeads have been developed. Also, the chemistry of the microsupport has been adapted in order to afford better protection of fragile cells to mechanical wear while simultaneously reorienting their differentiation towards the sought aims (production of cytokines, enzymes etc. ...). Future progress depends upon solutions being brought to problems inherent to this new technology (maintenance of steady state conditions of growth etc. ...) as well as to requirements arising from animal cell culture in general (biosensors, bioreactor’s design etc. ...). Besides such technical implementations, biology at large is also expected to benefit from the advent of microcarriers in fields as diverse as the preparation of metaphasic chromosomes in bulk, toxicity testing, organ reconstitution following cell transplantation etc. h.

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References

  1. Agius L, Battersby C, Alberti GMM (1985) In vitro Cell and Develop. Biol. 21: 254

    CAS  Google Scholar 

  2. Alternatives to animal use in research, testing and education. Congress of the United States. Office of Technological Assessment. Washington DC 20510, 1986

    Google Scholar 

  3. Anderson DC, Springer TA (1987) Ann. Rev. Med. 38: 175

    PubMed  CAS  Google Scholar 

  4. Arathoon WR, Birch JR (1986) Science 232: 1390

    PubMed  CAS  Google Scholar 

  5. Arathoon WR, Telling RC (1982) Develop. biol. Standard 50: 145

    CAS  Google Scholar 

  6. Auböck J, Romani N, Grubauer G, Fritsch P (1986) Brit. J. Dermatol. 114: 465

    Google Scholar 

  7. Baijot B, Duchene M, Stephenne J (1985) Develop. biol. Standard 66: 523

    Google Scholar 

  8. Barnes D, Sato G (1980) Cell 22: 649

    PubMed  CAS  Google Scholar 

  9. Barngrover D, Thomas J, Thilly WG (1985) J. Cell Sci. 78: 173

    PubMed  CAS  Google Scholar 

  10. Basham TY, Nickoloff BJ, Merigan TC, Morhenn VB (1984) J. Invest. Dermatol. 83: 88

    PubMed  CAS  Google Scholar 

  11. Benhamou J-P (1987) Presse médicale 16: 705

    CAS  Google Scholar 

  12. Ben-Zéev A (1986) TIBS 11: 478

    Google Scholar 

  13. Bertolero F, Kaighn ME, Camalier RF, Saffiotti U (1986) In vitro Cell Develop. Biol. 22: 423

    CAS  Google Scholar 

  14. Billig D, Clark JM, Ewell AJ, Carter CM, Gebb C (1984) Develop. biol. Standard 55: 67

    Google Scholar 

  15. Blackburn EH (1985) TIG. Jan. 8–12 p 8

    Google Scholar 

  16. Bohak Z, Kadouri A, Sussman MV, Feldman AF (1987) Biopolymers 26: S205

    Google Scholar 

  17. Boschetti E (1987) Personal communication

    Google Scholar 

  18. Boyce ST, Ham RG (1985) J. Tissue Cult. Meth. 9: 83

    Google Scholar 

  19. Brzeski H, Chambers M, MacDonald C, Stimson WH (1985) Develop. biol. Standard 60: 105

    CAS  Google Scholar 

  20. Burke D, Brown MJ, Jacobson BS (1983) Tiss. & Cell 15: 181

    CAS  Google Scholar 

  21. Collins J, Betz H, Davies JE, Fiers W, Paoletti E, Pfaff E, Rowlands DJ, Schallen H, Siewert G, Sippel AE, Wagner EF (1985) Animals and medicines. In: Silver S (ed) Biotechnology: potentials and limitations. Dahlem Konferenzen — Life Science Research Report 35 Springer-Verlag Berlin Heidelberg New York, p 127

    Google Scholar 

  22. Croughan MS, Hamel JF, Wang DIC (1987) Biotech. Bioeng. 29: 130

    Google Scholar 

  23. Delzer J, Hauser H, Lehmann J (1985) Develop. biol. Standard 60: 413

    CAS  Google Scholar 

  24. Demetriou AA, Whiting JF, Feldman D, Levenson SM, Chowdhury NR, Moscioni AD, Kram M, Chowdhury JR (1986) Science 233: 1190

    PubMed  CAS  Google Scholar 

  25. Dennis PA, Wolley R, Taylor NS, Moyer CF (1986) Cytometry 7: 384

    PubMed  CAS  Google Scholar 

  26. Dierickx PJ (1987) Arch. Intern. Physiol. Bioch. 95: B138

    Google Scholar 

  27. Dodet B (1986) Biofutur 52: 35

    Google Scholar 

  28. Faure M, Mauduit G, Schmitt D, Kanitakis J, Demidem A, Thivolet J (1987) Brit. J. Dermatol. 116: 161

    CAS  Google Scholar 

  29. Fiorentine D, Shahar A, Mizrahi A (1985) Develop. biol. Standard 60: 421

    CAS  Google Scholar 

  30. Fink A, Bibi H, Eliraz A, Tabachnik E, Bentwich Z (1985) Immunol. Lett. 10: 319

    PubMed  CAS  Google Scholar 

  31. Fleischaker RJ Jr, Sinskey AJ (1981) Europ. Appl. Microbiol. Biotechnol. 12: 193

    Google Scholar 

  32. Folkman J, Moscona A (1978) Nature 273: 345

    PubMed  CAS  Google Scholar 

  33. Folkman J, Klagsbrun M (1987) Science 235: 442

    PubMed  CAS  Google Scholar 

  34. Friedman SL, Roll FJ (1987) Anal. Biochem. 161: 207

    PubMed  CAS  Google Scholar 

  35. Furcht LT (1986) Lab. Invest. 55: 505

    PubMed  CAS  Google Scholar 

  36. Gannon F (1985) The choice of host organisms for industrial genetic engineering use. In: Production d’agents thérapeutiques par génie génétique. Joyeaux A, Leygue G, Morre M, Roncucci R, Schmelck PH (eds) Symposium Quo Vadis? 29–30th May 1985. Toulouse-Labège. France, p 45

    Google Scholar 

  37. Gene Transfer (1986) Kucherlapati R (ed) Plenum, New York

    Google Scholar 

  38. Goldberg AM (1987) The use of animal cells for evaluation of toxicity, carcinogenesis and mutagenesis. In: Spier RE, Griffiths JB (eds) Modern approaches to animal cell technology, 1st edn. p 747 Butterworths, UK

    Google Scholar 

  39. Gomes M, Schmitt D, Dezutter-Dambuyant C, Capara JD, Thivolet J (1985) Path. Biol. 34: 157

    Google Scholar 

  40. Griffiths JB, McEntee ID, Electricwala A, Atkinson A, Sutton PM, Naish S, Riley PA (1985) Develop. biol. Standard 60: 439

    CAS  Google Scholar 

  41. Griffiths JB (1985) Cell products: an overview. In: Spier RE, Griffiths JB (eds) Animal cell biotechnology, vol 2, p 3, Academic, New York

    Google Scholar 

  42. Griffiths PR (1983) Science 222: 297

    PubMed  CAS  Google Scholar 

  43. Groner Y, Lieman-Hurwitz J, Dafni N, Sherman L, Levanon D, Bernstein Y, Danciger E, Elroy-Stein O (1985) Ann. N.Y. Acad. Sci. 450: 133

    PubMed  CAS  Google Scholar 

  44. Hanotte O, Dejaiffe C, Dubois D, Vanderpoorten P, Menozzi FD, Miller AOA (1987) Biol. Cell 59: 175

    PubMed  CAS  Google Scholar 

  45. Harris H, Miller OJ, Klein G, Worst P, Tachibana T (1969) Nature 223: 363

    PubMed  CAS  Google Scholar 

  46. Hayflick L, Moorhead PS (1961) Exptl. Cell Res. 25: 585

    Google Scholar 

  47. Hayle AJ (1986) Arch Virol. 89: 81

    PubMed  CAS  Google Scholar 

  48. Higgins IJ(1987) Development and applications of amperometric biosensors. 18th FEBS Meeting. Ljubljana June 28–July 3

    Google Scholar 

  49. Hirtenstein M, Clark J (1980) In: Richards RR, Rajan K (eds), p 97 Pergamon, Oxford, UK

    Google Scholar 

  50. Hooper ML (1982) Biochim. Biophys. Acta 651: 85

    PubMed  CAS  Google Scholar 

  51. Hope J (1988) Perfusion cultures. In: Miller AOA (ed) Advances in animal cell technology, NATO Advanced Research Workshop. Brussels 21–24 Sept. 1987. Nijhoff Publ. (in preparation)

    Google Scholar 

  52. Hu WS, Giard DJ, Wang DIC (1985) Biotech. Bioeng. 27: 1466

    CAS  Google Scholar 

  53. Hu WS (1983) Doctoral disseration, Dept. Appl. Biol. Sci., M.I.T., Cambridge, MA

    Google Scholar 

  54. Hu WS, Meir J, Wang DIC (1985) Biotech. Bioeng. 27: 585

    Google Scholar 

  55. Jacobs JP, Jones CM, Baille JP (1980) Nature 227: 168

    Google Scholar 

  56. Jacobson BS, Ryan US (1982) Tiss & Cell. 14: 69

    CAS  Google Scholar 

  57. Jonasson J, Harris H (1977) J. Cell Sci. 24: 255

    PubMed  CAS  Google Scholar 

  58. Katayama H, Itami S, Koizumi H, Tsutsui M (1987) J. Invest. Dermatol. 88: 33

    PubMed  CAS  Google Scholar 

  59. Kaudewitz P, Ruzicka T, Meurer M, Braun-Falco O (1985) Arch. Dermatol. Res. 277: 444

    PubMed  CAS  Google Scholar 

  60. Klein TM, Wolff ED, Wu R, Sanford JC (1987) Nature 327: 70

    CAS  Google Scholar 

  61. Kotler M, Reuveny S, Mizrahi A, Shahar A (1985) Develop. biol. Standard 60: 255

    CAS  Google Scholar 

  62. Lawrance SK, Smith CL, Srivastava R, Cantor CR, Weissman SM (1987) Science 235: 1387

    PubMed  CAS  Google Scholar 

  63. Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EYHP (1987) Science 235: 1394

    PubMed  CAS  Google Scholar 

  64. Lewin R (1987) Science 236: 31

    Google Scholar 

  65. Lewin R (1987) Science 235: 747

    PubMed  CAS  Google Scholar 

  66. Lindskog U, Lundgren B, Billig D, Lindner E (1987) Develop. biol. Standard 66: 307

    CAS  Google Scholar 

  67. Lindner E, Arvidsson AC, Wergeland I, Billig D (1987) Develop. biol. Standard 66: 299

    CAS  Google Scholar 

  68. Litwin J (1985) Develop. biol. Standard 60: 237

    CAS  Google Scholar 

  69. Loo DT, Fuquay JI, Rawson CL, Barnes DW (1987) Science 236: 200

    PubMed  CAS  Google Scholar 

  70. Lydersen BK, Putnam J, Bognar E, Patterson M, Pugh GG, Noll LA (1985) The use of a ceramic matrix in a large scale cell culture system. In: Feder J, Tolbert WR (eds) Large-scale mammalian cell culture. Academic Press, New York, p 39

    Google Scholar 

  71. Mansbridge JN, Nickoloff BJ, Morhenn VB (1987) J. Invest. Dermatol. 88: 602

    PubMed  CAS  Google Scholar 

  72. Margel S (1983) Appl. Biochem. Biotechn. 8: 523

    CAS  Google Scholar 

  73. Maroudas NG (1973) Exptl. Cell Res. 81: 104

    PubMed  CAS  Google Scholar 

  74. Meigner B (1978) Develop. biol. Standard 42: 141

    Google Scholar 

  75. Merten OW, Palfi GE, Steiner J (1986) Adv. Biotechn. Proc. 6: 111

    CAS  Google Scholar 

  76. Merten OW, Palfi GE (1987) Biotech. Bioeng. 66: 111

    CAS  Google Scholar 

  77. Microcarrier cell culture. Principles and methods. Pharmacia Fine Chemicals AB. Technical literature 1981

    Google Scholar 

  78. Idem p 103

    Google Scholar 

  79. Miller AOA, Miller-Faurès A (1981) Develop. biol. Standard 50: 287

    CAS  Google Scholar 

  80. Miller-Faurès A, Blave A, Caudron M, Sené CL, Miller AOA (1985) Develop. biol. Standard 60: 209

    Google Scholar 

  81. Miller SJO, Henrotte M, Miller AOA (1986) Biotech. Bioeng. 28: 1466

    Google Scholar 

  82. Mitchell KJ, Wray W (1979) Exptl. Cell Res. 123: 452

    PubMed  CAS  Google Scholar 

  83. Mizrahi VA (1986) Bio/Technology 4: 123

    CAS  Google Scholar 

  84. Montagnon B, Vincent-Falquet JC, Fanget B (1984) Develop. biol. Standard 55: 37

    Google Scholar 

  85. Montagnon BJ (1985) Tropical and Geographical Med. 37: S40

    Google Scholar 

  86. Murray A, Szostak J (1988) Pour la Science 123: 60

    Google Scholar 

  87. Ng JJY, Crespi CL, Thilly WG (1980) Anal. Biochem. 109: 231

    PubMed  CAS  Google Scholar 

  88. Nichols WW, Murphy DG, Cristofalo VJ, Toji LH, Greene AE, Dwight SA (1976) Science 196: 60

    Google Scholar 

  89. Nilsson K, Buszaki F, Mosbach K (1986) Bio/Technology 4: 989

    Google Scholar 

  90. Nilsson K, Scheirer W, Merten OW, östberg L, Liehl E, Katinger HWD, Mosbach K (1983) Nature 302: 629

    PubMed  CAS  Google Scholar 

  91. Ohashi M, Aizawa S, Ooka H, Ohsawa T, Kaji K, Kondo H, Kobayashi T, Noumura T, Matsuo M, Mitsui Y, Murota S, Yamamoto K, Itoh H, Shimada H, Utakoji T (1980) Exptl. Geront. 15: 121

    CAS  Google Scholar 

  92. Olinger JM, Hill DM, Jakobsen RJ, Brody RS (1986) Biochim. Biophys. Acta 869: 89

    PubMed  CAS  Google Scholar 

  93. Peters D, Branschomb E, Dean P, Merrill T, Pinkel D, van Dilla M, Gray JW (1985) Cytometry 6: 290

    PubMed  CAS  Google Scholar 

  94. Petricciani JC, Salk J, Noguchi PD (1981) Develop. biol. Standard 50: 15

    CAS  Google Scholar 

  95. Petricciani JC (1985) The use of continuous cell lines in the manufacture of recombinant DNA products. In: Joyeaux A, Leygue G, Morra M, Roncucci R, Schmelck PH (eds) Production d’agents thérapeutiques par génie génétique Symposium Quo Vadis? 29–30th May. Toulouse-Labège. France, p 209

    Google Scholar 

  96. Petricciani JC (1987) The liberation of animal cells: psychology of changing attitudes. In: Spier RE, Griffiths JB (eds). Modern approaches to animal cell technology, 1st edn. p 1 Butterworth, UK

    Google Scholar 

  97. Pullen KF, Johnson MD, Phillips AW, Ball GD, Finter NB (1985) Develop. biol. Standard 60: 175

    CAS  Google Scholar 

  98. Rabits CA, Jarrell JA, Abraham EH (1987) J. Biol. Chem. 262: 1352

    Google Scholar 

  99. Ratafia M (1987) Bio/Technology 5: 692

    Google Scholar 

  100. Reuveny S, Silberstein L, Shahar A, Freeman E, Mizrahi A (1982) In Vitro 18: 92

    PubMed  CAS  Google Scholar 

  101. Reuveny S, Mizrahi A, Kotier M, Freeman A (1983) Biotech. Bioeng. 25: 2969

    CAS  Google Scholar 

  102. Reuveny S, Corett R, Freeman A, Kotier M, Mizrahi A (1985) Develop. biol. Standard 60: 243

    CAS  Google Scholar 

  103. Revel JP, Nicholson BJ, Yancey SB (1985) Ann. Rev. Physiol. 47: 263

    CAS  Google Scholar 

  104. Riordan ML (1987) Bio/Technology 5: 444

    Google Scholar 

  105. Rolin-Limbosch S, Moens W, Szpirer C (1986) Carcinogenesis 7: 1235

    PubMed  CAS  Google Scholar 

  106. Rupp RG (1985) Use of cellular microencapsulation in large-scale production of monoclonal antibodies. In: Feder J, Tolbert WR (eds) Large-scale mammalian cell culture. Academic Press, New York, p 19

    Google Scholar 

  107. Ryan US, Mortara M, Whitaker C (1980) Tiss. Cell 4: 619

    Google Scholar 

  108. Sanford KK, Earle WR, Evans VJ, Waltz HK, Shannon JE (1951) J. Nat. Cancer Inst. 11: 773

    PubMed  CAS  Google Scholar 

  109. Scaggiante B, Pineschi B, Sustersich M, Andolina M, Agosti E, Romeo D (1987) Transplantation 44: 59

    PubMed  CAS  Google Scholar 

  110. Scheynius A, Johansson C, van der Meide PH (1986) Brit. J. Dermatol. 115: 543

    CAS  Google Scholar 

  111. Schlaeger EJ, Eggimann B, Gast A (1987) Develop. biol. Standard 66: 403

    CAS  Google Scholar 

  112. Schönherr OT, van Gelder PTJA, van Hees PJ, van Os AMJM, Roelofs HMW (1987) Develop. biol. Standard 66: 211

    Google Scholar 

  113. Schulz R, Krafft H, Piehl GW, Lehmann J (1985) Develop. biol. Standard 66: 489

    Google Scholar 

  114. Scott FJ (1985) A search for alternatives to animal testing. Biotechnol. Lab. April 4–5

    Google Scholar 

  115. Seizinger BR, Rouleau G, Ozelius LJ, Lane AH, St. George-Hyslop P, Huson S, Gusella JF, Martuza RL (1987) Science 236: 317

    PubMed  CAS  Google Scholar 

  116. Shahar A, Mizrahi A, Reuveny S, Zinman T, Shainberg A (1985) Develop. biol. Standard 60: 236

    Google Scholar 

  117. Sharma SK (1986) Separat Sci. Technol. 21: 701

    CAS  Google Scholar 

  118. Selden RF, Skokiewicz MJ, Howie KB, Russell PS, Goodman HM (1987) Science 236: 714

    PubMed  CAS  Google Scholar 

  119. Shopsis C, Sathe S (1984) Toxicology 29: 195

    PubMed  CAS  Google Scholar 

  120. Simhony S, Kosower EM, Katzir A (1986) Appl. Phys. Lett. 49: 253

    CAS  Google Scholar 

  121. Simhony S, Kosower EM, Katzir A (1987) Biochem. Biophys. Res. Comm. 142: 1059

    PubMed  CAS  Google Scholar 

  122. Terasima T, Tolmach LJ (1963) Exptl. Cell Res. 30: 344

    PubMed  CAS  Google Scholar 

  123. Thebline D, Harfield J, Hanotte O, Dubois D, Miller AOA (1987) Develop. biol. Standard (submitted for publication)

    Google Scholar 

  124. Thivolet J (1986) La peau de remplacement. Pour la Science Mars, p 16

    Google Scholar 

  125. Thivolet J, Faure M, Demidem A, Mauduit G (1986) Bull. Acad. Natl. Med. 170: 557

    PubMed  CAS  Google Scholar 

  126. Thomson DMP, Phelan K, Scanzano R, Fink A (1982) Intern. J. Cancer 30: 311

    CAS  Google Scholar 

  127. Tolbert WR, Lewis C Jr, White PJ, Feder J (1985) Perfusion culture systems for production of mammalian cell biomolecules. In: Feder J, Tolbert WR (eds) Large-scale mammalian cell culture. Academic Press, New York, p 97

    Google Scholar 

  128. Uren J (1985) The recovery of genetically engineered mammalian proteins. Intern. Biotech. Lab. April, 26

    Google Scholar 

  129. Van Brunt J (1986) Bio/Technology 4: 835

    Google Scholar 

  130. Van Brunt J (1987) Bio/Technology 5: 199

    Google Scholar 

  131. Van Brunt J (1987) Bio/Technology 5: 313

    Google Scholar 

  132. Van Brunt J (1987) Bio/Technology 5: 437

    Google Scholar 

  133. Van der Ploeg LHT (1987) Separation of chromosome-sized DNA molecules by pulsed field gel electrophoresis. Biotechn. Lab. April, p 8

    Google Scholar 

  134. van Wezel AL (1967) Nature 216: 64

    PubMed  Google Scholar 

  135. van Wezel AL (1973) Microcarrier cultures of animal cells. In: Kruse PF, Patterson MK (eds) Tissue Culture: Methods and Applications. Academic Press, New York, p 372

    Google Scholar 

  136. Varani J, Dame M, Beals TF, Wass JA (1983) Biotech. Bioeng. 25: 1359

    Google Scholar 

  137. Varani J, Dame M, Rediske J, Beals TF, Hillegas W (1985) J. Biol. Standard 13: 67

    CAS  Google Scholar 

  138. Varani J, Hasday JD, Sitrin RG, Brubaker PG, Hillegas WI (1986) In vitro 22: 575

    CAS  Google Scholar 

  139. Vitkauskas GV, Canellakis ES (1985) Biochem. Biophys. Acta 823: 19

    PubMed  CAS  Google Scholar 

  140. Vlodavsky I, Lui GM, Gospodarowicz D (1982) Cell 19: 607

    Google Scholar 

  141. Volc-Platzer B, Leibl H, Luger T, Zohn G Stingl G (1985) J. Invest. Dermatol. 85: 16

    PubMed  CAS  Google Scholar 

  142. Wang HY (1984) Biotech. Bioeng. Symp. 14: 601

    Google Scholar 

  143. Watt FM (1986) TIBS 11: 482

    CAS  Google Scholar 

  144. Waymouth C (1984) Preparation and use of serum-free culture media. In: Sibarsku DW, Sato GH (eds) Cell culture methods for molecular and cell biology, vol 1, p 23, Alan R. Liss, New York

    Google Scholar 

  145. Weissman BE, Saxon PJ, Pasquale SR, Jones GR, Geiser AG, Stanbridge EJ (1987) Science 236: 175

    PubMed  CAS  Google Scholar 

  146. Whiteside JP, Spier RE (1985) Develop. biol. Standard 60: 305

    CAS  Google Scholar 

  147. Widell A, Hansson BG, Nordenfeit E (1984) Virol. Meth. 8: 63

    CAS  Google Scholar 

  148. Wiemann MC, Creswick B, Calabresi P (1985) Cellular and biochemical aspects of human tumor cell growth and function in hollow fiber culture. In: Feder J, Tolbert WR (eds) Largescale mammalian cell culture. Academic Press, New York, p 125

    Google Scholar 

  149. Wiener F, Klein G, Harris H (1971) J. Cell Sci. 8: 681

    PubMed  Google Scholar 

  150. Wilson T (1984) FDA loosens restraints on cell substrates Bio/Technology, October, p 842

    Google Scholar 

  151. Wong H, Chang TMS (1986) Intern. J. Artif. Organs 9: 335

    CAS  Google Scholar 

  152. Young MW, Dean RC (1987) Bio/Technology 5: 835

    CAS  Google Scholar 

  153. Zieve GW, Turnbull D, Mullins JM, McIntosh JR (1980) Exptl. Cell Res. 126: 397

    PubMed  CAS  Google Scholar 

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Miller, A.O.A., Menozzi, F.D., Dubois, D. (1989). Microbeads and anchorage-dependent eukaryotic cells: The beginning of a new era in biotechnology. In: Vertebrate Cell Culture II and Enzyme Technology. Advances in Biochemical Engineering/Biotechnology, vol 39/1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/BFb0051952

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