52. Chen AK-L, Reuveny S, Oh SKW (2013) Application of human mesenchymal and pluripotent
stem cell microcarrier cultures in cellular therapy: achievements and future direction.
Biotechnol Adv 31:1032–1046. https://doi.org/10.1016/j.biotechadv.2013.03.006
53. Jossen V, van den Bos C, Eibl R, Eibl D (2018) Manufacturing human mesenchymal stem
cells at clinical scale: process and regulatory challenges. Appl Microbiol Biotechnol
102:3981–3994. https://doi.org/10.1007/s00253-018-8912-x
54. Rafiq QA, Ruck S, Hanga MP, Heathman TRJ, Coopman K, Nienow AW, Williams DJ,
Hewitt CJ (2018) Qualitative and quantitative demonstration of bead-to-bead transfer with
bone marrow-derived human mesenchymal stem cells on microcarriers: utilising the phenomenon to improve culture performance. Biochem Eng J 135:11–21. https://doi.org/10.1016/j.
bej.2017.11.005
55. Leber J, Barekzai J, Blumenstock M, Pospisil B, Salzig D, Czermak P (2017) Microcarrier
choice and bead-to-bead transfer for human mesenchymal stem cells in serum-containing and
chemically defined media. Process Biochem 59:255–265. https://doi.org/10.1016/j.procbio.
2017.03.017
56. Szczypka M, Splan D, Woolls H, Brandwein H (2014) Single-use bioreactors and
microcarriers. Bioprocess Int 12:54–64
57. Zhao L-G, Chen S-L, Teng Y-J, An L-P, Wang J, Ma J-L, Xia Y-Y (2014) The MEK5/ERK5
pathway mediates fluid shear stress promoted osteoblast differentiation. Connect Tissue Res
55:96–102. https://doi.org/10.3109/03008207.2013.853755
58. Yim EK, Sheetz MP (2012) Force-dependent cell signaling in stem cell differentiation. Stem
Cell Res Ther 3:41. https://doi.org/10.1186/scrt132
59. Frauenschuh S, Reichmann E, Ibold Y, Goetz PM, Sittinger M, Ringe J (2007) A microcarrierbased cultivation system for expansion of primary mesenchymal stem cells. Biotechnol Prog
23:187–193. https://doi.org/10.1021/bp060155w
60. Panchalingam KM, Jung S, Rosenberg L, Behie LA (2015) Bioprocessing strategies for the
large-scale production of human mesenchymal stem cells: a review. Stem Cell Res Ther 6:225.
https://doi.org/10.1186/s13287-015-0228-5
61. Ferrari C, Balandras F, Guedon E, Olmos E, Chevalot I, Marc A (2012) Limiting cell
aggregation during mesenchymal stem cell expansion on microcarriers. Biotechnol Prog
28:780–787. https://doi.org/10.1002/btpr.1527
62. Schirmaier C, Jossen V, Kaiser SC, Jüngerkes F, Brill S, Safavi-Nab A, Siehoff A, van den
Bos C, Eibl D, Eibl R (2014) Scale-up of adipose tissue-derived mesenchymal stem cell
production in stirred single-use bioreactors under low-serum conditions. Eng Life Sci
14:292–303. https://doi.org/10.1002/elsc.201300134
63. Lawson T, Kehoe DE, Schnitzler AC, Rapiejko PJ, Der KA, Philbrick K, Punreddy S,
Rigby S, Smith R, Feng Q, Murrell JR, Rook MS (2017) Process development for expansion
of human mesenchymal stromal cells in a 50L single-use stirred tank bioreactor. Biochem Eng
J 120:49–62. https://doi.org/10.1016/j.bej.2016.11.020
64. Gruber R, Karreth F, Kandler B, Fuerst G, Rot A, Fischer AB (2004) Platelet-released
supernatants increase migration and proliferation, and decrease osteogenic differentiation of
bone marrow-derived mesenchymal progenitor cell under in vitro conditions. Platelets
15:29–35
65. Lange C, Cakiroglu F, Spiess AN, Cappallo-Obermann H, Dierlamm J, Zander AR (2007)
Accelerated and safe expansion of human mesenchymal stromal cells in animal serum-free
medium for transplantation and regenerative medicine. J Cell Physiol 213:18–26
66. Abdelrazik H, Spaggiari GM, Chiossone L, Mretta L (2011) Mesenchymal stem cells
expanded in human platelet lysate display a decreased inhibitory capacity on T- and NK-cell
proliferation and function. Eur J Immunol 41:3281–3290
67. Heathman TRJJ, Glyn VAM, Picken A, Rafiq QA, Coopman K, Nienow AW, Kara B, Hewitt
CJ (2015) Expansion, harvest and cryopreservation of human mesenchymal stem cells in a
serum-free microcarrier process. Biotechnol Bioeng 112:1696–1707. https://doi.org/10.1002/
bit.25582
Numerical Methods for the Design and Description of In Vitro Expansion. . .
225
stem cell microcarrier cultures in cellular therapy: achievements and future direction.
Biotechnol Adv 31:1032–1046. https://doi.org/10.1016/j.biotechadv.2013.03.006
53. Jossen V, van den Bos C, Eibl R, Eibl D (2018) Manufacturing human mesenchymal stem
cells at clinical scale: process and regulatory challenges. Appl Microbiol Biotechnol
102:3981–3994. https://doi.org/10.1007/s00253-018-8912-x
54. Rafiq QA, Ruck S, Hanga MP, Heathman TRJ, Coopman K, Nienow AW, Williams DJ,
Hewitt CJ (2018) Qualitative and quantitative demonstration of bead-to-bead transfer with
bone marrow-derived human mesenchymal stem cells on microcarriers: utilising the phenomenon to improve culture performance. Biochem Eng J 135:11–21. https://doi.org/10.1016/j.
bej.2017.11.005
55. Leber J, Barekzai J, Blumenstock M, Pospisil B, Salzig D, Czermak P (2017) Microcarrier
choice and bead-to-bead transfer for human mesenchymal stem cells in serum-containing and
chemically defined media. Process Biochem 59:255–265. https://doi.org/10.1016/j.procbio.
2017.03.017
56. Szczypka M, Splan D, Woolls H, Brandwein H (2014) Single-use bioreactors and
microcarriers. Bioprocess Int 12:54–64
57. Zhao L-G, Chen S-L, Teng Y-J, An L-P, Wang J, Ma J-L, Xia Y-Y (2014) The MEK5/ERK5
pathway mediates fluid shear stress promoted osteoblast differentiation. Connect Tissue Res
55:96–102. https://doi.org/10.3109/03008207.2013.853755
58. Yim EK, Sheetz MP (2012) Force-dependent cell signaling in stem cell differentiation. Stem
Cell Res Ther 3:41. https://doi.org/10.1186/scrt132
59. Frauenschuh S, Reichmann E, Ibold Y, Goetz PM, Sittinger M, Ringe J (2007) A microcarrierbased cultivation system for expansion of primary mesenchymal stem cells. Biotechnol Prog
23:187–193. https://doi.org/10.1021/bp060155w
60. Panchalingam KM, Jung S, Rosenberg L, Behie LA (2015) Bioprocessing strategies for the
large-scale production of human mesenchymal stem cells: a review. Stem Cell Res Ther 6:225.
https://doi.org/10.1186/s13287-015-0228-5
61. Ferrari C, Balandras F, Guedon E, Olmos E, Chevalot I, Marc A (2012) Limiting cell
aggregation during mesenchymal stem cell expansion on microcarriers. Biotechnol Prog
28:780–787. https://doi.org/10.1002/btpr.1527
62. Schirmaier C, Jossen V, Kaiser SC, Jüngerkes F, Brill S, Safavi-Nab A, Siehoff A, van den
Bos C, Eibl D, Eibl R (2014) Scale-up of adipose tissue-derived mesenchymal stem cell
production in stirred single-use bioreactors under low-serum conditions. Eng Life Sci
14:292–303. https://doi.org/10.1002/elsc.201300134
63. Lawson T, Kehoe DE, Schnitzler AC, Rapiejko PJ, Der KA, Philbrick K, Punreddy S,
Rigby S, Smith R, Feng Q, Murrell JR, Rook MS (2017) Process development for expansion
of human mesenchymal stromal cells in a 50L single-use stirred tank bioreactor. Biochem Eng
J 120:49–62. https://doi.org/10.1016/j.bej.2016.11.020
64. Gruber R, Karreth F, Kandler B, Fuerst G, Rot A, Fischer AB (2004) Platelet-released
supernatants increase migration and proliferation, and decrease osteogenic differentiation of
bone marrow-derived mesenchymal progenitor cell under in vitro conditions. Platelets
15:29–35
65. Lange C, Cakiroglu F, Spiess AN, Cappallo-Obermann H, Dierlamm J, Zander AR (2007)
Accelerated and safe expansion of human mesenchymal stromal cells in animal serum-free
medium for transplantation and regenerative medicine. J Cell Physiol 213:18–26
66. Abdelrazik H, Spaggiari GM, Chiossone L, Mretta L (2011) Mesenchymal stem cells
expanded in human platelet lysate display a decreased inhibitory capacity on T- and NK-cell
proliferation and function. Eur J Immunol 41:3281–3290
67. Heathman TRJJ, Glyn VAM, Picken A, Rafiq QA, Coopman K, Nienow AW, Kara B, Hewitt
CJ (2015) Expansion, harvest and cryopreservation of human mesenchymal stem cells in a
serum-free microcarrier process. Biotechnol Bioeng 112:1696–1707. https://doi.org/10.1002/
bit.25582
Numerical Methods for the Design and Description of In Vitro Expansion. . .
225