Electrospun Rapamycin-Eluting Polyurethane Fibers for Vascular Grafts

ABSTRACT

Purpose

To develop rapamycin-eluting electrospun polyurethane (PU) vascular grafts that could effectively suppress local smooth muscle cell (SMC) proliferation.

Methods

Rapamycin (RM) was incorporated in PU fibers by blend electrospinning using three distinct blending methods. The drug release profiles and the bioavailability of RM-containing PU fibers in the form of fibrous mats and vascular grafts were evaluated up to 77 days in vitro.

Results

RM-contained PU fibers generated by the three distinct blending methods exhibited significantly different fiber diameters (200–500 nm) and distinct RM release kinetics. Young’s moduli of the electrospun fibrous mats increased with higher RM contents and decreased with larger fiber diameters. For all blending methods, RM release kinetics was characteristic of a Fickian diffusion for at least 77 days in vitro. RM-PU fibers generated via powder blending showed the highest encapsulation efficiency. The RM in grafts made of these fibers remained bioactive and was still able to inhibit smooth muscle cell proliferation after 77 days of continual in vitro release.

Conclusions

Electrospun RM-containing PU fibers can serve as effective drug carriers for the local suppression of SMC proliferation and could be used as RM-eluting scaffolds for vascular grafts.

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Abbreviations

AB:

almarBlue

BSA:

bovine serum albumin

DMEM:

Dulbecco’s Modified of Eagle’s Medium

FBS:

fetal bovine serum

HFP-1:

1, 1, 3, 3, 3-Hexafluoro-2-Propanol

HPLC:

high performance liquid chromatography

NS-IP:

normal saline-isopropyl alcohol solution

PANi:

polyaniline

PBS:

phosphate buffered saline

PGE:

PLGA-gelatin-elastin

PLGA:

poly(lactic-co-glycolic acid)

PTCA:

percutaneous transluminal coronary angioplasty

PU:

polyurethane

RM:

rapamycin

SMC:

smooth muscle cell

SPU:

segmented polyurethane

TCP:

tissue culture polystyrene

REFERENCES

  1. 1.

    Liu MW, Roubin GS, King III SB. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation. 1989;79:1374–87.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Fattori R, Piva T. Drug-eluting stents in vascular intervention. Lancet. 2003;361:247–9.

    PubMed  Article  Google Scholar 

  3. 3.

    Allaire E, Clowes AW. Endothelial cell injury in cardiovascular surgery: the intimal hyperplastic response. Ann Thorac Surg. 1997;63:582–91.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med. 2007;356:998–1008.

    Google Scholar 

  5. 5.

    Kim YH, Park SW, Lee SW, Park DW, Yun SC, Lee CW, et al. Sirolimus-eluting stent versus paclitaxel-eluting stent for patients with long coronary artery disease. Circulation. 2006;114:2148–53.

    Google Scholar 

  6. 6.

    Adelman SJ. Sirolimus and its analogs and its effects on vascular diseases. Curr Pharm Des. 2010;16:4002–11.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Wang X, Venkatraman SS, Boey FY, Loo JS, Tan LP. Controlled release of sirolimus from a multilayered PLGA stent matrix. Biomaterials. 2006;27:5588–95.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Luong-Van E, Grondahl L, Chua KN, Leong KW, Nurcombe V, Cool SM. Controlled release of heparin from poly(epsilon-caprolactone) electrospun fibers. Biomaterials. 2006;27:2042–50.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Khan W, Farah S, Domb AJ. Drug eluting stents: developments and current status. J Control Release. 2012;161:703–12.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Biondi M, Ungaro F, Quaglia F, Netti PA. Controlled drug delivery in tissue engineering. Adv Drug Deliv Rev. 2008;60:229–42.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Kowalczyk T, Nowicka A, Elbaum D, Kowalewski TA. Electrospinning of bovine serum albumin. Optimization and the use for production of biosensors. Biomacromolecules. 2008;9:2087–90.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Montero RB, Vial X, Nguyen DT, Farhand S, Reardon M, Pham SM, et al. bFGF-containing electrospun gelatin scaffolds with controlled nano-architectural features for directed angiogenesis. Acta Biomater. 2012;8:1778–91.

    Google Scholar 

  13. 13.

    Ekaputra AK, Prestwich GD, Cool SM, Hutmacher DW. The three-dimensional vascularization of growth factor-releasing hybrid scaffold of poly (epsilon-caprolactone)/collagen fibers and hyaluronic acid hydrogel. Biomaterials. 2011;32:8108–17.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Hyung II RM, Kim JS, Konno T, Takai M, Ishihara K. Preparation of electrospun poly(L-lactide-co-caprolactone-co-glycolide)/phospholipid polymer/rapamycin blended fibers for vascular application. Curr Appl Phys. 2009;9:249–51.

    Article  Google Scholar 

  15. 15.

    Okuda T, Tominaga K, Kidoaki S. Time-programmed dual release formulation by multilayered drug-loaded nanofiber meshes. J Control Release. 2010;143:258–64.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Xie J, Wang CH. Electrospun micro- and nanofibers for sustained delivery of paclitaxel to treat C6 glioma in vitro. Pharm Res. 2006;23:1817–26.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Cui W, Li X, Zhu X, Yu G, Zhou S, Weng J. Investigation of drug release and matrix degradation of electrospun poly(DL-lactide) fibers with paracetanol inoculation. Biomacromolecules. 2006;7:1623–9.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Li M, Guo Y, Wei Y, MacDiarmid AG, Lelkes PI. Electrospinning polyaniline-contained gelatin nanofibers for tissue engineering applications. Biomaterials. 2006;27:2705–15.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Li M, Mondrinos MJ, Chen X, Gandhi MR, Ko FK, Lelkes PI. Co-electrospun poly(lactide-co-glycolide), gelatin, and elastin blends for tissue engineering scaffolds. J Biomed Mater Res A. 2006;79:963–73.

    PubMed  Google Scholar 

  20. 20.

    Uttayarat P, Perets A, Li M, Pimton P, Stachelek SJ, Alferiev I, et al. Micropatterning of three-dimensional electrospun polyurethane vascular grafts. Acta Biomater. 2010;6:4229–37.

    Google Scholar 

  21. 21.

    Crapo PM, Wang Y. Physiologic compliance in engineered small-diameter arterial constructs based on an elastomeric substrate. Biomaterials. 2010;31:1626–35.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Han J, Lazarovici P, Pomerantz C, Chen X, Wei Y, Lelkes PI. Co-electrospun blends of PLGA, gelatin, and elastin as potential nonthrombogenic scaffolds for vascular tissue engineering. Biomacromolecules. 2011;12:399–408.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Naseerali CP, Hari PR, Sreenivasan K. The release kinetics of drug eluting stents containing sirolimus as coated drug: role of release media. J Chromatogr B Anal Technol Biomed Life Sci. 2010;878:709–12.

    Article  CAS  Google Scholar 

  24. 24.

    Okner R, Oron M, Tal N, Nyska A, Kumar N, Mandler D, et al. Electrocoating of stainless steel coronary stents for extended release of paclitaxel. J Biomed Mater Res A. 2009;88:427–36.

    Google Scholar 

  25. 25.

    Uttayarat P, Chen M, Li M, Allen FD, Composto RJ, Lelkes PI. Microtopography and flow modulate the direction of endothelial cell migration. Am J Physiol Heart Circ Physiol. 2008;294:H1027–1035.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Mack MJ, Banning AP, Serruys PW, Morice MC, Taeymans Y, Van Nooten G, et al. Bypass versus drug-eluting stents at three years in SYNTAX patients with diabetes mellitus or metabolic syndrome. Ann Thorac Surg. 2011;92:2140–6.

    Google Scholar 

  27. 27.

    Barner HB. Status of percutaneous coronary intervention and coronary artery bypass. Eur J Cardio-Thorac. 2006;30:419–24.

    Google Scholar 

  28. 28.

    Mo XM, Xu CY, Kotaki M, Ramakrishna S. Electrospun P(LLA-CL) nanofiber: a biomimetic extracellular matrix for smooth muscle cell and endothelial cell proliferation. Biomaterials. 2004;25:1883–90.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Zong X, Kim K, Fang D, Ran S, Hsiao B, Chu B. Structure and process relationship of electrospun bioabsorbable nanofiber membranes. Polymer. 2002;43:4403–12.

    Article  CAS  Google Scholar 

  30. 30.

    He SW, Li SS, Hu ZM, Yu JR, Chen L, Zhu J. Effects of three parameters on the diameter of electrospun poly(ethylene oxide) nanofibers. J Nanosci Nanotechnol. 2011;11:1052–9.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Han J, Chen TX, Branford-White CJ, Zhu LM. Electrospun shikonin-loaded PCL/PTMC composite fiber mats with potential biomedical applications. Int J Pharm. 2009;382:215–21.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Desai K, Kit K, Li J, Zivanovic S. Morphological and surface properties of electrospun chitosan nanofibers. Biomacromolecules. 2008;9:1000–6.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Gandhi PJ, Murthy ZVP. Solubility and crystal size of sirolimus in different organic solvents. J Chem Eng Data. 2010;55:5050–4.

    Article  CAS  Google Scholar 

  34. 34.

    Tan EP, Ng SY, Lim CT. Tensile testing of a single ultrafine polymeric fiber. Biomaterials. 2005;26:1453–6.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Ferron GM, Jusko WJ. Species differences in sirolimus stability in humans, rabbits, and rats. Drug Metab Dispos. 1998;26:83–4.

    Google Scholar 

  36. 36.

    Simamora P, Alvarez JM, Yalkowsky SH. Solubilization of rapamycin. Int J Pharm. 2001;213:25–9.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Verreck G, Chun I, Rosenblatt J, Peeters J, Dijck AV, Mensch J, et al. Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer. J Control Release. 2003;92:349–60.

    Google Scholar 

  38. 38.

    Yang Y, Li X, Cui W, Zhou S, Tan R, Wang C. Structural stability and release profiles of proteins from core-shell poly (DL-lactide) ultrafine fibers prepared by emulsion electrospinning. J Biomed Mater Res A. 2008;86:374–85.

    PubMed  Google Scholar 

  39. 39.

    Huatan H, Collett JH, Attwood D, Booth C. Preparation and characterization of poly(epsilon-caprolactone) polymer blends for the delivery of proteins. Biomaterials. 1995;16:1297–303.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Innocente F, Mandracchia D, Pektok E, Nottelet B, Tille JC, de Valence S, et al. Paclitaxel-eluting biodegradable synthetic vascular prostheses: a step toward reduction of neointima formation? Circulation. 2009;120(11 Suppl):S37–45.

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ACKNOWLEDGEMENTS AND DISCLOSURES

Jingjia Han and Shady Farah equally contributed to this paper. This work was supported by a translational research grant by HUB (DU/BIOMED-IDR/HUJI) from Drexel University and The Hebrew University of Jerusalem. We thank Dr. Gozde Senel-Ayaz (Drexel BIOMED) for her assistance with SEM and Dr. Wahid Khan (IDR) for his assistance with developing the analytical method used to assess drug release.

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Correspondence to Abraham J. Domb or Peter I. Lelkes.

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Han, J., Farah, S., Domb, A.J. et al. Electrospun Rapamycin-Eluting Polyurethane Fibers for Vascular Grafts. Pharm Res 30, 1735–1748 (2013). https://doi.org/10.1007/s11095-013-1016-5

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KEY WORDS

  • drug release
  • electrospinning
  • rapamycin
  • restenosis
  • smooth muscle cell