Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Nanoliter-scale synthesis of arrayed biomaterials and application to human embryonic stem cells

Abstract

Identification of biomaterials that support appropriate cellular attachment, proliferation and gene expression patterns is critical for tissue engineering and cell therapy. Here we describe an approach for rapid, nanoliter-scale synthesis of biomaterials and characterization of their interactions with cells. We simultaneously characterize over 1,700 human embryonic stem cell–material interactions and identify a host of unexpected materials effects that offer new levels of control over human embryonic stem cell behavior.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Biomaterial microarray design.
Figure 2: hES cells grown on polymer arrays.
Figure 3: 'Hit' polymer effects on hES cell attachment, growth and proliferation.
Figure 4: hES cells grown on 'hit' arrays.

Similar content being viewed by others

References

  1. Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Streuli, C. Extracellular matrix remodelling and cellular differentiation. Curr. Opin. Cell Biol. 11, 634–640 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Saltzman, W.M. in Principles of Tissue Engineering, edn. 2 (eds. Lanza, R.P., Langer, R.S. & Vacanti, J.) 221–235 (Academic Press, San Diego, 2000).

    Book  Google Scholar 

  4. Lanza, R.P., Langer, R.S. & Vacanti, J. (eds.) Principles of Tissue Engineering, edn. 2 (Academic Press, San Diego, 2000).

    Google Scholar 

  5. Chen, R.R. & Mooney, D.J. Polymeric growth factor delivery strategies for tissue engineering. Pharm. Res. 20, 1103–1112 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Sakiyama-Elbert, S.E. & Hubbell, J.A. Functional biomaterials: Design of novel biomaterials. Annu. Rev. Mater. Res. 31, 183–201 (2001).

    Article  CAS  Google Scholar 

  7. Fisher, J.P., Dean, D., Engel, P.S. & Mikos, A.G. Photoinitiated polymerization of biomaterials. Annu. Rev. Mater. Res. 31, 171–181 (2001).

    Article  CAS  Google Scholar 

  8. Folkman, J. & Moscona, A. Role of cell shape in growth control. Nature 273, 345–349 (1978).

    Article  CAS  PubMed  Google Scholar 

  9. Moll, R., Franke, W.W., Schiller, D.L., Geiger, B. & Krepler, R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31, 11–24 (1982).

    Article  CAS  PubMed  Google Scholar 

  10. Abraham, V.C., Taylor, D.L. & Haskins, J.R. High content screening applied to large-scale cell biology. Trends Biotechnol. 22, 15–22 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Burkoth, A.K., Burdick, J. & Anseth, K.S. Surface and bulk modifications to photocrosslinked polyanhydrides to control degradation behavior. J. Biomed. Mater. Res. 51, 352–359 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Hern, D.L. & Hubbell, J.A. Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing. J. Biomed. Mater. Res. 39, 266–276 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. MacBeath, G., Koehler, A.N. & Schreiber, S.L. Printing small molecules as microarrays and detecting protein-ligand interactions en masse. J. Am. Chem. Soc. 121, 7967–7968 (1999).

    Article  CAS  Google Scholar 

  14. MacBeath, G. & Schreiber, S.L. Printing proteins as microarrays for high-throughput function determination. Science 289, 1760–1763 (2000).

    CAS  PubMed  Google Scholar 

  15. Schena, M., Shalon, D., Davis, R.W. & Brown, P.O. Quantitative monitoring of gene-expression patterns with a complementary-DNA microarray. Science 270, 467–470 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Thomson, J.A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Levenberg, S., Golub, J.S., Amit, M., Itskovitz-Eldor, J. & Langer, R. Endothelial cells derived from human embryonic stem cells. Proc. Natl. Acad. Sci. USA 99, 4391–4396 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yaffe, D. & Saxel, O. Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle. Nature 270, 725–727 (1977).

    Article  CAS  PubMed  Google Scholar 

  19. Levenberg, S. et al. Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Proc. Natl. Acad. Sci. USA 100, 12741–12746 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank David Putnam, David Lynn, David Lavan and Daniel Kohane for helpful advice, Mara Macdonald for help with cell culture and Joseph Itskovitz-Eldor for assistance and cooperation in conducting this research. We would also like to thank Sean Milton and the BioMicro Center for help with slide analysis. This work was supported by the National Science Foundation (through the MIT Biotechnology Process and Engineering Center) and the National Institutes of Health (grant no. HL60435).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert Langer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

C2C12 cells grown on polymer arrays. (PDF 104 kb)

Supplementary Fig. 2

Design of “hit” Polymer arrays (PDF 214 kb)

Supplementary Fig. 3

Standard deviation of Cell coverage on Different Materials (PDF 118 kb)

Supplementary Fig. 4

Cells per spot with RA, on day one (PDF 82 kb)

Supplementary Fig. 5

Cells per spot with RA, on day six (PDF 81 kb)

Supplementary Table 1

Percent cells cytokeratin 7 positive on different materials over time (PDF 26 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anderson, D., Levenberg, S. & Langer, R. Nanoliter-scale synthesis of arrayed biomaterials and application to human embryonic stem cells. Nat Biotechnol 22, 863–866 (2004). https://doi.org/10.1038/nbt981

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt981

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing