Skip to main content
Log in

Chemical activation and changes in surface morphology of poly(ε-caprolactone) modulate VEGF responsiveness of human endothelial cells

  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

The high degree of clinical routine in percutaneous transluminal coronary angioplasty (PTCA) with and without stenting has not changed the fact that a large number of coronary heart disease patients are still affected by post-operative complications such as restenosis and thrombosis. Because re-endothelialization is the crucial aspect of wound healing after cardiovascular implant surgery, there is a need for modern biomaterials to aid endothelial cells in their adhesion and functional recovery post-stenting. This study systematically examines the potential of numerous chemical polymer modifications with regard to endothelialization. Poly(ε-caprolactone) (PCL) and its chemically activated forms are investigated in detail, as well as the impact of polymer surface morphology and precoating with matrix protein. Human umbilical vein endothelial cells (HUVECs) are used to characterize endothelial cell responses in terms of in vitro viability and adhesion. As a potential component in drug eluting implants, VEGF is applied as stimulus to boost endothelial cell proliferation on the polymer. In conclusion, plasma chemical activation of PCL combined with VEGF stimulation best enhances in vitro endothelialization. Examining the impact of morphological, chemical and biological modifications of PCL, this study makes an important new contribution towards the existing body of work on polymer endothelialization.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Dudash LA, Kligman F, Sarett SM, Kottke-Marchant K, Marchant RE. Endothelial cell attachment and shear response on biomimetic polymer-coated vascular grafts. J Biomed Mater Res. 2012;100(8):2204–10.

    Article  Google Scholar 

  2. Waterhouse A, Wise SG, Yin Y, Wu B, James B, Zreiqat H, et al. In vivo biocompatibility of a plasma-activated, coronary stent coating. Biomaterials. 2012;33(32):7984–92.

    Article  Google Scholar 

  3. Wu KK, Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annu Rev Med. 1996;47:315–31.

    Article  Google Scholar 

  4. He Q, Zhao Y, Chen B, Xiao Z, Zhang J, Chen L, et al. Improved cellularization and angiogenesis using collagen scaffolds chemically conjugated with vascular endothelial growth factor. Acta Biomater. 2011;7(3):1084–93.

    Article  Google Scholar 

  5. Jukema JW, Verschuren JJW, Ahmed TAN, Quax PHA. Restenosis after PCI. Part 1: pathophysiology and risk factors. Nat Rev Cardiol. 2011;9(1):53–62.

    Article  Google Scholar 

  6. Sternberg K, Grabow N, Petersen S, Weitschies W, Harder C, Ince H, et al. Advances in coronary stent technology-active drug-loaded stent surfaces for prevention of restenosis and improvement of biocompatibility. Curr Pharm Biotechnol. 2013;14(1):76–90.

    Google Scholar 

  7. Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol. 2010;56(23):1897–907.

    Article  Google Scholar 

  8. Wykrzykowska JJ, Onuma Y, Serruys PW. Advances in stent drug delivery: the future is in bioabsorbable stents. Expert Opin Drug Deliv. 2009;6(2):113–26.

    Article  Google Scholar 

  9. Pitt CG, Gratzl MM, Kimmel GL, Surles J, Schindler A. Aliphatic polyesters II. The degradation of poly (DL-lactide), poly (epsilon-caprolactone), and their copolymers in vivo. Biomaterials. 1981;2(4):215–20.

    Article  Google Scholar 

  10. Sun H, Mei L, Song C, Cui X, Wang P. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials. 2006;27(9):1735–40.

    Article  Google Scholar 

  11. Berneel E, Desmet T, Declercq H, Dubruel P, Cornelissen M. Double protein-coated poly-ε-caprolactone scaffolds: successful 2D to 3D transfer. J Biomed Mater Res. 2012;100(7):1783–91.

    Article  Google Scholar 

  12. Pektok E, Nottelet B, Tille J, Gurny R, Kalangos A, Moeller M, et al. Degradation and healing characteristics of small-diameter poly(ε-caprolactone) vascular grafts in the rat systemic arterial circulation. Circulation. 2008;118(24):2563–70.

    Article  Google Scholar 

  13. Wulf K, Teske M, Löbler M, Luderer F, Schmitz K, Sternberg K. Surface functionalization of poly(ε-caprolactone) improves its biocompatibility as scaffold material for bioartificial vessel prostheses. J Biomed Mater Res. 2011;98(1):89–100.

    Article  Google Scholar 

  14. Jiao Y, Cui F. Surface modification of polyester biomaterials for tissue engineering. Biomed Mater. 2007;2(4):24–7.

    Article  Google Scholar 

  15. Goddard J, Hotchkiss J. Polymer surface modification for the attachment of bioactive compounds. Prog Polym Sci. 2007;32(7):698–725.

    Article  Google Scholar 

  16. Isenberg BC, Williams C, Tranquillo RT. Engineering of small-diameter vessels. In: Atala A, Lanza R, Thomson JA, Nerem R, editors. Principles of regenerative medicine. 2nd ed. New York: Academic Press; 2011. p. 853–75.

    Chapter  Google Scholar 

  17. de Mel A, Jell G, Stevens MM, Seifalian AM. Biofunctionalization of biomaterials for accelerated in situ endothelialization: a review. Biomacromolecules. 2008;9(11):2969–79.

    Article  Google Scholar 

  18. Lin Q, Ding X, Qiu F, Song X, Fu G, Ji J. In situ endothelialization of intravascular stents coated with an anti-CD34 antibody functionalized heparin–collagen multilayer. Biomaterials. 2010;31(14):4017–25.

    Article  Google Scholar 

  19. Cooper T, Sefton M. Fibronectin coating of collagen modules increases in vivo HUVEC survival and vessel formation in SCID mice. Acta Biomater. 2011;7(3):1072–83.

    Article  Google Scholar 

  20. Adiguzel E, Ahmad PJ, Franco C, Bendeck MP. Collagens in the progression and complications of atherosclerosis. Vasc Med. 2009;14(1):73–89.

    Article  Google Scholar 

  21. Çelebi B, Mantovani D, Pineault N. Effects of extracellular matrix proteins on the growth of haematopoietic progenitor cells. Biomed Mater. 2011;6(5):55011.

    Article  Google Scholar 

  22. Tersteeg C, Roest M, Mak-Nienhuis EM, Ligtenberg E, Hoefer IE, Groot PG, et al. A fibronectin-fibrinogen-tropoelastin coating reduces smooth muscle cell growth but improves endothelial cell function. J Cell Mol Med. 2012;16(9):2117–26.

    Article  Google Scholar 

  23. von der Mark K, Park J, Bauer S, Schmuki P. Nanoscale engineering of biomimetic surfaces: cues from the extracellular matrix. Cell Tissue Res. 2010;339(1):131–53.

    Article  Google Scholar 

  24. Hirashima M. Regulation of endothelial cell differentiation and arterial specification by VEGF and Notch signaling. Anat Sci Int. 2009;84(3):95–101.

    Article  Google Scholar 

  25. Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011;437(2):169–83.

    Article  Google Scholar 

  26. Davies N, Dobner S, Bezuidenhout D, Schmidt C, Beck M, Zisch AH, et al. The dosage dependence of VEGF stimulation on scaffold neovascularisation. Biomaterials. 2008;29(26):3531–8.

    Article  Google Scholar 

  27. Swanson N, et al. In vitro evaluation of vascular endothelial growth factor (VEGF)-eluting stents. Int J Cardiol. 2003;92(2–3):247–51.

    Article  Google Scholar 

  28. Asahara T, Bauters C, Pastore C, Kearney M, Rossow S, Bunting S, et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation. 1995;91(11):2793–801.

    Article  Google Scholar 

  29. van Belle E, Tio FO, Couffinhal T, Maillard L, Passeri J, Isner JM. Stent endothelialization: time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine expedition. Circulation. 1997;95(2):438–48.

    Article  Google Scholar 

  30. Byth H, Mchunu BI, Dubery IA, Bornman L. Assessment of a simple, non-toxic alamar blue cell survival assay to monitor tomato cell viability. Phytochem Anal. 2001;12(5):340–6.

    Article  Google Scholar 

  31. Dunkern TR, Kaina B. Cell proliferation and DNA breaks are involved in ultraviolet light-induced apoptosis in nucleotide excision repair-deficient Chinese hamster cells. Mol Biol Cell. 2002;13(1):348–61.

    Article  Google Scholar 

  32. Kamath S, Bhattacharyya D, Padukudru C, Timmons RB, Tang L. Surface chemistry influences implant-mediated host tissue responses. J Biomed Mater Res. 2008;86(3):617–26.

    Article  Google Scholar 

  33. Ertel SI, Ratner BD, Horbett TA. Radiofrequency plasma deposition of oxygen-containing films on polystyrene and poly(ethylene terephthalate) substrates improves endothelial cell growth. J Biomed Mater Res. 1990;24(12):1637–59.

    Article  Google Scholar 

  34. Knetsch ML, Koole LH. VEGF-E enhances endothelialization and inhibits thrombus formation on polymeric surfaces. J Biomed Mater Res. 2010;93(1):77–85.

    Google Scholar 

  35. Wang HG, Yin TY, Ge SP, Zhang Q, Dong QL, Lei DX, et al. Biofunctionalization of titanium surface with multilayer films modified by heparin-VEGF-fibronectin complex to improve endothelial cell proliferation and blood compatibility. J Biomed Mater Res. 2013;101(2):413–20.

    Article  Google Scholar 

  36. Siow KS, Britcher L, Kumar S, Griesser HJ. Plasma methods for the generation of chemically reactive surfaces for biomolecule immobilization and cell colonization—a review. Plasma Process Polym. 2006;3(6–7):392–418.

    Article  Google Scholar 

  37. Pompe T, Keller K, Mothes G, Nitschke M, Teese M, Zimmermann R, et al. Surface modification of poly(hydroxybutyrate) films to control cell-matrix adhesion. Biomaterials. 2007;28(1):28–37.

    Article  Google Scholar 

  38. Yang J, Zeng Y, Zhang C, Chen Y, Yang Z, Li Y, et al. The prevention of restenosis in vivo with a VEGF gene and paclitaxel co-eluting stent. Biomaterials. 2013;34(6):1635–43.

    Article  Google Scholar 

  39. Curcio A, Torella D, Indolfi C. Mechanisms of smooth muscle cell proliferation and endothelial regeneration after vascular injury and stenting: approach to therapy. Circ J. 2011;75(6):1287–96.

    Article  Google Scholar 

  40. Walter DH. Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: an alternative strategy for inhibition of restenosis. Circulation. 2004;110(1):36–45.

    Article  Google Scholar 

  41. Weymann A, Schmack B, Okada T, Soos P, et al. Reendothelialization of human heart valve neoscaffolds using umbilical cord-derived endothelial cells. Circ J. 2013;77(1):207–16.

    Article  Google Scholar 

  42. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8(2):128–35.

    Article  Google Scholar 

  43. Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet. 2007;370(9591):937–48.

    Article  Google Scholar 

  44. Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol. 2007;27(7):1500–10.

    Article  Google Scholar 

  45. van Dyck CJ, Hoymans VY, Haine S, Vrints CJ. New-generation drug-eluting stents: focus on Xience V® everolimus-eluting stent and Resolute® zotarolimus-eluting stent. J Int Cardiol. 2013;26(3):278–86.

    Article  Google Scholar 

  46. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest. 1983;49(3):327–33.

    Google Scholar 

  47. Davies MJ, Woolf N, Rowles PM, Pepper J. Morphology of the endothelium over atherosclerotic plaques in human coronary arteries. Heart. 1988;60(6):459–64.

    Article  Google Scholar 

  48. Jeremy JY, Rowe D, Emsley AM, Newby AC. Nitric oxide and the proliferation of vascular smooth muscle cells. Cardiovasc Res. 1999;43(3):580–94.

    Article  Google Scholar 

  49. Castellot J. Cultured endothelial cells produce heparinlike inhibitor of smooth muscle cell growth. J Cell Biol. 1981;90(2):372–9.

    Article  Google Scholar 

  50. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83(5):1774–7.

    Article  Google Scholar 

  51. Tahir H, Bona-Casas C, Hoekstra AG, Wong KKL. Modelling the effect of a functional endothelium on the development of in-stent restenosis. PLoS One. 2013;8(6):e66138.

    Article  Google Scholar 

Download references

Acknowledgments

This work was funded by the German federal government via the BMBF project REMEDIS “Höhere Lebensqualität durch neuartige Mikroimplantate” (FKZ: 03IS2081).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thilo Storm.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Storm, T., Wulf, K., Teske, M. et al. Chemical activation and changes in surface morphology of poly(ε-caprolactone) modulate VEGF responsiveness of human endothelial cells. J Mater Sci: Mater Med 25, 2003–2015 (2014). https://doi.org/10.1007/s10856-014-5226-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10856-014-5226-0

Keywords

Navigation