Skip to main content
SpringerLink
Log in

Fabrication of uniform-sized poly-ɛ-caprolactone microspheres and their applications in human embryonic stem cell culture

  • Published:
Biomedical Microdevices Aims and scope Submit manuscript

Abstract

The generation of liquefied poly-ɛ-caprolactone (PCL) droplets by means of a microfluidic device results in uniform-sized microspheres, which are validated as microcarriers for human embryonic stem cell culture. Formed droplet size and size distribution, as well as the resulting PCL microsphere size, are correlated with the viscosity and flow rate ratio of the dispersed (Q d) and continuous (Q c) phases. PCL in dichloromethane increases its viscosity with concentration and molecular weight. Higher viscosity and Q d/Q c lead to the formation of larger droplets, within two observed formation modes: dripping and jetting. At low viscosity of dispersed phase and Q d/Q c, the microfluidic device is operated in dripping mode, which generates droplets and microspheres with greater size uniformity. Solutions with lower molecular weight PCL have lower viscosity, resulting in a wider concentration range for the dripping mode. When coated with extracellular matrix (ECM) proteins, the fabricated PCL microspheres are demonstrated capable of supporting the expansion of human embryonic stem cells.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • M. Anindita, P. Vikas, Res. J. Biotechnol. 2, 58 (2007)

    Google Scholar 

  • A. Arshi, Y. Nakashima, H. Nakano, S. Eaimkhong, D. Evseenko, J. Reed, A.Z. Stieg, J.K. Gimzewski, A. Nakano, Sci. Technol. Adv. Mater. 14, 025003 (2013)

    Article  Google Scholar 

  • F. Bai, X.L. Yang, R. Li, B. Huang, W.Q. Huang, Polymer 47, 5775 (2006)

    Article  Google Scholar 

  • F. Bai, B. Huang, X.L. Yang, W.Q. Huang, Polymer 48, 3641 (2007)

    Article  Google Scholar 

  • A. Baji, S.C. Wong, T.S. Srivatsan, G.O. Njus, G. Mathur, Mater. Manuf. Process. 21, 211 (2006)

    Article  Google Scholar 

  • L. Barad, R. Schick, N. Zeevi-Levin, J. Itskovitz-Eldor, O. Binah, Can. J. Cardiol. 30, 1279 (2014)

    Article  Google Scholar 

  • C. Bardouille, J. Lehmann, P. Heimann, H. Jockusch, Appl. Microbiol. Biotechnol. 55, 556 (2001)

    Article  Google Scholar 

  • E. Baruch-Teblum, Y. Mastai, K. Landfester, Eur. Polym. J. 46, 1671 (2010)

    Article  Google Scholar 

  • T. Basinska, S. Slomkowski, J. Biomater. Sci. Polym. Ed. 3, 115 (1991)

    Article  Google Scholar 

  • G. Baydemir, M. Odabasi, Artif. Cells Nanomed. Biotechnol. 41, 319 (2013)

    Article  Google Scholar 

  • S.L. Beaucage, Curr. Med. Chem. 8, 1213 (2001)

    Article  Google Scholar 

  • R. Bodmeier, J.W. McGinity, Int. J. Pharm. 43, 179 (1988)

    Article  Google Scholar 

  • L. Borque, C. Maside, A. Rus, J. del Cura, J. Clin. Immunoass. 17, 160 (1994)

    Google Scholar 

  • P. Boudreault, J.P. Tremblay, M.-F. Pépin, A. Garnier, J. Biotechnol. 9, 63 (2001)

    Article  Google Scholar 

  • M. Bouquey, C. Serra, N. Berton, L. Prat, G. Hadziioannou, Chem. Eng. J. 135, S93 (2008)

    Article  Google Scholar 

  • J.L. Brown, L.S. Nair, C.T. Laurencin, J. Biomed Mater. Res. B Appl. Biomater. 86B, 396 (2008)

    Article  Google Scholar 

  • C. Cadic, C. Baquey, B. Dupuy, Polym. J. 23, 933 (1991)

    Article  Google Scholar 

  • L. Chang, C. Peng, P. Chiang, H. Wang, T. Luo, Eur. J. Nucl. Med. Mol. Imaging 40, S247 (2013)

    Google Scholar 

  • X.G. Chen, C.S. Liu, C.G. Liu, X.H. Meng, C.M. Lee, H.J. Park, Biochem. Eng. J. 27, 269 (2006)

    Article  Google Scholar 

  • A.K.L. Chen, X.L. Chen, Y.M. Lim, S. Reuveny, S.K.W. Oh, Tissue Eng. C Methods 20, 227 (2014)

    Article  Google Scholar 

  • C.H. Choi, J.H. Jung, Y.W. Rhee, D.P. Kim, S.E. Shim, C.S. Lee, Biomed. Microdevices 9, 855 (2007)

    Article  Google Scholar 

  • C. Chung, E. Anderson, R.R. Pera, B.L. Pruitt, S.C. Heilshorn, Soft Matter 8, 10141 (2012)

    Article  Google Scholar 

  • C. Cramer, P. Fischer, E.J. Windhab, Chem. Eng. Sci. 59, 3045 (2004)

    Article  Google Scholar 

  • T.K. Dash, V.B. Konkimalla, J. Control. Release 158, 15 (2012)

    Article  Google Scholar 

  • E.B. Denkbaş, A.S. Hoffman, E. Pişkin, Chem. Eng. J. Biochem. Eng. J. 58, 65 (1995)

    Article  Google Scholar 

  • B. Dhandayuthapani, Y. Yoshida, T. Maekawa, D.S. Kumar, Int. J. Polym. Sci. 2011, 290602 (2011)

    Article  Google Scholar 

  • D.E. Discher, P. Janmey, Y.L. Wang, Science 310, 1139 (2005)

    Article  Google Scholar 

  • J.S. Doctor, S. Salvaterra, D. Vitrant, K. Azari, M.A. Ihnat, J.O. Hollinger, P. Campbell, Dev. Biol. 235, 245 (2001)

    Google Scholar 

  • P.F. Dong, J.H. Xu, H. Zhao, G.S. Luo, Chem. Eng. J. 214, 106 (2013)

    Article  Google Scholar 

  • P. Ducheyne, T. Livingston, I. Shapiro, P. Ayyaswamy, H. Gao, S. Radin, Tissue Eng. 3, 219 (1997)

    Article  Google Scholar 

  • A.J. Engler, S. Sen, H.L. Sweeney, D.E. Discher, Cell 126, 677 (2006)

  • N. Eroshenko, R. Ramachandran, V.K. Yadavalli, R.R. Rao, J. Biol. Eng. 7, 7 (2013)

    Article  Google Scholar 

  • D.J. Foran, F. Cahn, E.F. Eikenberry, Anal. Quant. Cytol. Histol. 13, 215 (1991)

    Google Scholar 

  • L. Gepstein, Circ. Res. 91, 866 (2002)

    Article  Google Scholar 

  • J. Godbee, E. Scott, P. Pattamunuch, S. Chen, E. Mathiowitz, J. Microencapsul. 21, 151 (2004)

    Article  Google Scholar 

  • B. Hallmark, C. Parmar, D. Walker, C.H. Hornung, M.R. Mackley, J.F. Davidson, Chem. Eng. Sci. 64, 4758 (2009)

    Article  Google Scholar 

  • GE Healthcare, Amersham biosciences. Microcarrier cell culture: Principles and methods. (GE Healthcare/Amersham Biosciences, 2005), pp. 20

  • B.C. Heng, J. Li, A.K.L. Chen, S. Reuveny, S.M. Cool, W.R. Birch, S.K.W. Oh, Stem Cells Dev. 21, 1701 (2012)

    Article  Google Scholar 

  • Y.P. Hong, F.J. Wang, Microfluid. Nanofluid. 3, 341 (2007)

    Article  Google Scholar 

  • S.J. Hong, H.S. Yu, H.W. Kim, Macromol. Biosci. 9, 639 (2009)

    Article  Google Scholar 

  • S. Huang, Y.J. Wang, T.Z. Deng, F. Jin, S.X. Liu, Y.J. Zhang, F. Feng, Y. Jin, J. Alloys Compd. 460, 639 (2008)

    Article  Google Scholar 

  • G.Z. Jin, J.H. Park, S.J. Seo, H.W. Kim, Biotechnol. Lett. 36, 1539 (2014)

    Article  Google Scholar 

  • S.A. Kelly, A.G. Grant, Cell Biol. Int. Rep. 6, 733 (1982)

    Article  Google Scholar 

  • A.J. Keung, P. Asuri, S. Kumarz, D.V. Schaffer, Integr. Biol. 4, 1049 (2012)

    Article  Google Scholar 

  • J.V. Koleske, R.D. Lundberg, J. Polym. Sci. B Polym. Phys. 7, 795 (1969)

    Article  Google Scholar 

  • T. Konry, R.B. Hayman, D.R. Walt, Anal. Chem. 81, 5777 (2009)

    Article  Google Scholar 

  • A.T. Lam, J. Li, A.K.L. Chen, S. Reuveny, S.K.W. Oh, W.R. Birch, Stem Cells Dev. 23, 1688 (2014a)

    Article  Google Scholar 

  • A.T. Lam, A.K.L. Chen, J. Li, W.R. Birch, S. Reuveny, S.K.W. Oh, Stem Cell Res. Ther. 5, 110 (2014b)

    Article  Google Scholar 

  • H. Landgren, P. Sartipy, Expert Opin. Drug Discovery 9, 9 (2014)

    Article  Google Scholar 

  • M.R. Lee, K.W. Kwon, H. Jung, H.N. Kim, K.Y. Suh, K. Kim, K.S. Kim, Biomaterials 31, 4360 (2010)

    Article  Google Scholar 

  • S. Lee, J. Kim, T.J. Park, Y. Shin, S.Y. Lee, Y.M. Han, S. Kang, H.S. Park, Biomaterials 32, 8816 (2011)

    Article  Google Scholar 

  • H.W. Leung, A. Chen, A.B.H. Choo, S. Reuveny, S.K.W. Oh, Tissue Eng. C Methods 17, 165 (2001)

    Article  Google Scholar 

  • M. Li, O. Rouaud, D. Poncelet, Int. J. Pharm. 363, 26 (2008)

    Article  Google Scholar 

  • J. Li, J. Bardy, L.Y.W. Yap, A. Chen, V. Nurcombe, S.M. Cool, S.K.W. Oh, W.R. Birch, Biointerphases 5, FA132 (2010)

    Article  Google Scholar 

  • Q. Lin, Y.P. Cai, M.L. Yuan, L. Ma, M.F. Qiu, J. Su, Oncol. Rep. 32, 2405 (2014)

    Google Scholar 

  • Y. Liu, T.P. Russell, M.G. Samant, J. Stöhr, H.R. Brown, A. Cossy-Favre, J. Diaz, Macromolecules 30, 7768 (1997)

    Article  Google Scholar 

  • L.T. Lock, E.S. Tzanakakis, Tissue Eng. A 15, 2051 (2009)

    Article  Google Scholar 

  • J. Malda, C.G. Frondoza, Trends Biotechnol. 24, 299 (2006)

    Article  Google Scholar 

  • J. Malda, E. Kreijveld, J.S. Temenoff, C.A. van Blitterswijk, J. Riesle, Biomaterials 24, 5153 (2003)

    Article  Google Scholar 

  • S. Margel, Appl. Biochem. Biotechnol. 8, 523 (1983)

    Article  Google Scholar 

  • S. Margel, J. Chromatogr. A 462, 177 (1989)

    Article  Google Scholar 

  • Y. Martin, M. Eldardiri, D.J. Lawrence-Watt, J.R. Sharpe, Tissue Eng. B Rev. 17, 71 (2011)

    Article  Google Scholar 

  • J.V. McGivern, A.D. Ebert, Adv. Drug Deliv. Rev. 69, 170 (2014)

    Article  Google Scholar 

  • T.X. Miao, K.S. Rao, J.L.R.A. Spees, J. Control. Release 192, 57 (2014)

    Article  Google Scholar 

  • A.V. Murueva, A.M. Shershneva, E.I. Shishatskaya, T.G. Volova, Bull. Exp. Biol. Med. 157, 597 (2014)

    Article  Google Scholar 

  • S. Musah, S.A. Morin, P.J. Wrighton, D.B. Zwick, S. Jin, L.L. Kiessling, ACS Nano 6, 10168 (2012)

    Article  Google Scholar 

  • Y. Nie, V. Bergendahl, D.J. Hei, J.M. Jones, S.P. Palecek, Biotechnol. Prog. 25, 20 (2009)

    Article  Google Scholar 

  • S.G. Nir, R. David, M. Zaruba, W.M. Franz, J. Itskovitz-Eldor, Cardiovasc. Res. 58, 313 (2003)

    Article  Google Scholar 

  • P.B. O’Donnell, J.W. McGinity, Adv. Drug Deliv. Rev. 28, 25 (1997)

    Article  Google Scholar 

  • S.K.W. Oh, A.K. Chen, Y. Mok, X. Chen, U.M. Lim, A. Chin, A.B.H. Choo, S. Reuveny, Stem Cell Res. 2, 219 (2009)

    Article  Google Scholar 

  • G.E. Park, M.A. Pattison, K. Park, T.J. Webster, Biomaterials 26, 3075 (2005)

    Article  Google Scholar 

  • R.A. Perez, A. El-Fiqi, J.H. Park, T.H. Kim, J.H. Kim, H.W. Kim, Acta Biomater. 10, 520 (2014)

    Article  Google Scholar 

  • S. Reuveny, L. Silberstein, A. Shahar, E. Freeman, A. Mizrahi, In Vitro Cell Dev. Biol. 18, 92 (1982)

    Article  Google Scholar 

  • C.B. Roth, J.R. Dutcher, J. Electroanal. Chem. 584, 13 (2005)

    Article  Google Scholar 

  • L. Sang, Y.P. Hong, F.J. Wang, Microfluid. Nanofluid. 6, 621 (2009)

    Article  Google Scholar 

  • K. Saralidze, L.H. Koole, M.L.W. Knetsch, Materials 3, 3537 (2010)

    Article  Google Scholar 

  • J.T. Schantz, D.W. Hutmacher, K.W. Ng, H.L. Khor, T.C. Lim, S.H. Teoh, Int. J. Oral Maxillofac. Implants 17, 161 (2002)

    Google Scholar 

  • M. Seo, Z. Nie, S. Xu, P.C. Lewis, E. Kumacheva, Langmuir 21, 4773 (2005)

    Article  Google Scholar 

  • C.A. Serra, Z.Q. Chang, Chem. Eng. Technol. 31, 1099 (2008)

    Article  Google Scholar 

  • C. Serra, N. Berton, M. Bouquey, L. Prat, G. Hadziioannou, Langmuir 23, 7745 (2007)

    Article  Google Scholar 

  • M.C. Serrano, R. Pagani, J. Pena, M. Vallet-Regi, J.V. Comas, M.T. Portoles, J. Tissue Eng. Regen. Med. 5, 238 (2011)

    Article  Google Scholar 

  • Y.B. Sun, L.G. Villa-Diaz, R.H.W. Lam, W.Q. Chen, P.H. Krebsbach, J.P. Fu, PLoS ONE 7, e37178 (2012)

    Article  Google Scholar 

  • J.A. Thomson, Science 282, 1827 (1998)

    Article  Google Scholar 

  • S. Tielens, H. Declercq, T. Gorski, E. Lippens, E. Schacht, M. Cornelissen, Biomacromolecules 8, 825 (2007)

    Article  Google Scholar 

  • J.W. Tom, P.G. Debenedetti, R. Jerome, J. Supercrit. Fluids 7, 9 (1994)

    Article  Google Scholar 

  • J.X. Wang, R. Ye, Y.H. Wei, H.H. Wang, X.J. Xu, F. Zhang, J. Qu, B.Q. Zuo, H.X. Zhang, J. Biomed. Mater. Res. A 100A, 632 (2012)

    Article  Google Scholar 

  • S.S.Y. Wong, H.S. Bernstein, Regen. Med. 5, 763 (2010)

    Article  Google Scholar 

  • M.A. Woodruff, D.W. Hutmacher, Prog. Polym. Sci. 35, 1217 (2010)

    Article  Google Scholar 

  • J.H. Xu, S.W. Li, C. Tostado, W.J. Lan, G.S. Luo, Biomed. Microdevices 11, 243 (2009a)

    Article  Google Scholar 

  • Q. Xu, M. Hashimoto, T.T. Dang, T. Hoare, D.S. Kohane, G.M. Whitesides, R. Langer, D.G. Anderson, Small 5, 1575 (2009b)

    Article  Google Scholar 

  • C.Y. Yang, S.Y. Tsay, R.C.C. Tsiang, J. Microencapsul. 18, 223 (2001a)

    Article  Google Scholar 

  • Y.Y. Yang, T.S. Chung, N.P. Ng, Biomaterials 22, 231 (2001b)

    Article  Google Scholar 

  • L.Y.W. Yap, J. Li, I.Y. Phang, L.T. Ong, J.Z.E. Ow, J.C.H. Goh, V. Nurcombe, J. Hobley, A.B.H. Choo, S.K.W. Oh, S.M. Cool, W.R. Birch, Tissue Eng. C Methods 17, 209 (2011)

    Article  Google Scholar 

  • A. Yeo, E. Sju, B. Rai, S.H. Teoh, J. Biomed Mater. Res. B Appl. Biomater. 87B, 562 (2008)

    Article  Google Scholar 

  • D.F. Zhang, H.A. Stone, Phys. Fluids 9, 2234 (1997)

    Article  Google Scholar 

  • H. Zhang, S.Y. Tong, X.Z. Zhang, S.X. Cheng, R.X. Zhuo, H. Li, J. Phys. Chem. C 111, 12681 (2007)

    Article  Google Scholar 

  • Q.C. Zhang, K. Tan, Z.Y. Ye, Y. Zhang, W.S. Tan, M.D. Lang, Mater. Sci. Eng. C Mater. Biol. Appl. 32, 2589 (2012)

    Article  Google Scholar 

  • J. Zhang, D. Wang, J.C. Pan, J. Wang, H.B. Zhao, Q. Li, X.H. Zhou, J. Mol. Catal. B Enzym. 104, 29 (2014)

    Article  Google Scholar 

  • L.P. Zhu, Y.G. Li, Q.H. Zhang, H.Z. Wang, M.F. Zhu, Biomed. Microdevices 12, 169 (2010)

    Article  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge funding from the Joint Council Office, as well as support from the Institute of Materials Research and Engineering and the Bioprocessing Technology Institute of the Agency for Science, Technology and Research (A*STAR), Singapore.

Author information

Authors and Affiliations

  1. A*STAR (Agency for Science, Technology and Research), Institute of Materials Research and Engineering, 2 Fusionopolis Way, Innovis, #08-03, Singapore, 138634, Singapore

    Jian Li, Jessica Pei Wen Toh & William R. Birch

  2. A*STAR (Agency for Science, Technology and Research), Bioprocessing Technology Institute, 20 Biopolis Way, #06-01, Singapore, 138668, Singapore

    Alan Tin-Lun Lam, Shaul Reuveny & Steve Kah-Weng Oh

Authors
  1. Jian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Tin-Lun Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jessica Pei Wen Toh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shaul Reuveny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steve Kah-Weng Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William R. Birch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William R. Birch.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Lam, A.TL., Toh, J.P.W. et al. Fabrication of uniform-sized poly-ɛ-caprolactone microspheres and their applications in human embryonic stem cell culture. Biomed Microdevices 17, 105 (2015). https://doi.org/10.1007/s10544-015-0010-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s10544-015-0010-6

Keywords

Search

Navigation