Controlled growth factor release from synthetic extracellular matrices

Abstract

Polymeric matrices can be used to grow new tissues and organs1,2, and the delivery of growth factors from these matrices is one method to regenerate tissues3,4. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels5,6, is that most drug delivery systems have been designed to operate under static conditions. We thought that polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments. Critical design features for this type of system include the ability to undergo repeated deformation, and a reversible binding of the protein growth factors to polymeric matrices to allow for responses to repeated stimuli. Here we report a model delivery system that can respond to mechanical signalling and upregulate the release of a growth factor to promote blood vessel formation. This approach may find a number of applications, including regeneration and engineering of new tissues and more general drug-delivery applications.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: In vitro release profile of VEGF from alginate hydrogels under mechanical stimulation.
Figure 2: In vivo response to VEGF released from alginate hydrogels under mechanical stimulation.
Figure 3: Quantitative analysis of granulation tissue formed in SCID mice.
Figure 4: In vivo response to VEGF-loaded hydrogels implanted into femoral artery ligation site of NOD mice.

References

  1. 1

    Langer, R. & Vacanti, J. P. Tissue engineering. Science 260, 920–926 ( 1993).

  2. 2

    Putnam, A. J. & Mooney, D. J. Tissue engineering using synthetic extracellular matrices. Nature Med. 2, 824 –826 (1996).

  3. 3

    Shea, L. D., Smiley, E., Bonadio, J. & Mooney, D. J. DNA delivery from polymer matrices for tissue engineering. Nature Biotechnol. 17, 551–554 ( 1999).

  4. 4

    Ripamonti, U. & Reddi, A. H. Tissue engineering, morphogenesis, and regeneration of the periodontal tissues by bone morphogenetic proteins. Crit. Rev. Oral Biol. Med. 8, 154– 163 (1997).

  5. 5

    Kim, B.-S., Nikolovski, J., Bonadio, J. & Mooney, D. J. Cyclic mechanical strain regulates the development of engineered smooth muscle tissue. Nature Biotechnol. 17, 979– 983 (1999).

  6. 6

    Niklason, L. E. et al. Functional arteries grown in vitro. Science 284, 489–493 ( 1999).

  7. 7

    Vlodavsky, I. et al. Extracellular sequestration and release of fibroblast growth factor: a regulatory mechanism? Trends Biochem. Sci. 16, 268–271 (1991).

  8. 8

    Neufeld, G., Cohen, T., Gengrinovitch, S. & Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13, 9–22 ( 1999).

  9. 9

    Baldwin, S. P. & Saltzman, W. M. Materials for protein delivery in tissue engineering. Adv. Drug Delivery Rev. 33, 71–86 (1998).

  10. 10

    Jen, A. C., Wake, M. C. & Mikos, A. G. Hydrogels for cell immobilization. Biotechnol. Bioeng. 50, 357–364 ( 1996).

  11. 11

    Plate, K. H., Breiser, G., Weich, H. A. & Risau, W. Vascular endothelial growth factor is a potential tumor angiogenesis factor in vivo. Nature 359, 845– 848 (1992).

  12. 12

    Chicurel, M. E., Chen, C. S. & Ingber, D. E. Cellular control lies in the balance of forces. Curr. Opin. Cell Biol. 10, 232–239 (1998).

  13. 13

    Williams, B. Mechanical influences on vascular smooth muscle cell function. J. Hypertension 16, 1921–1929 (1998).

  14. 14

    Langer, R. Drug delivery and targeting. Nature 392 (suppl.), 5–10 (1998).

  15. 15

    Wang, C., Stewart, R. J. & Kopecek, J. Hybrid hydrogels assembled from synthetic polymers and coiled-coil protein domains. Nature 397, 417–420 (1999).

  16. 16

    Chen, G. & Hoffman, A. S. Graft copolymers that exhibit temperature-induced phase transition over a wide range of pH. Nature 373, 49–52 ( 1995).

  17. 17

    Mitragorti, S., Blankschtein, D. & Langer, R. Ultrasound-mediated transdermal protein delivery. Science 269, 850–853 ( 1995).

  18. 18

    Kwon, I. C., Bae, Y. H. & Kim, S. W. Electrically erodible polymer gel for controlled release of drugs. Nature 354, 291– 293 (1991).

  19. 19

    Edelman, E., Brown, L. & Langer, R. In vitro and in vivo kinetics of regulated drug release from polymer matrices by oscillating magnetic fields. J. Biomed. Mater. Res. 21, 339–353 (1987).

  20. 20

    Nör, J. E., Christensen, J., Mooney, D. J. & Polverini, P. J. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of BCL-2 expression. Am. J. Pathol. 152, 375– 384 (1999).

Download references

Acknowledgements

We thank the National Institutes of Health for financial support of this research. M.C.P. acknowledges the Whitaker Foundation for a graduate fellowship.

Author information

Correspondence to David J. Mooney.

Supplementary information

Supplementary Figures 1 and 2 (DOC 96 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.