Skip to main content

Advertisement

SpringerLink
Log in

Controlled Delivery of Fibroblast Growth Factor-9 from Biodegradable Poly(ester amide) Fibers for Building Functional Neovasculature

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

For building functional vasculature, controlled delivery of fibroblast growth factor-9 (FGF9) from electrospun fibers is an appealing strategy to overcome challenges associated with its short half-life. FGF9 sustained delivery could potentially drive muscularization of angiogenic sprouts and help regenerate stable functional neovasculature in ischemic vascular disease patients.

Methods

Electrospinning parameters of FGF9-loaded poly(ester amide) (PEA) fibers have been optimized, using blend and emulsion electrospinning techniques. In vitro PEA matrix degradation, biocompatibility, FGF9 release kinetics, and bioactivity of the released FGF9 were evaluated. qPCR was employed to evaluate platelet-derived growth factor receptor-β (PDGFRβ) gene expression in NIH-3T3 fibroblasts, 10T1/2 cells, and human coronary artery smooth muscle cells cultured on PEA fibers at different FGF9 concentrations.

Results

Loaded PEA fibers exhibited controlled release of FGF9 over 28 days with limited burst effect while preserving FGF9 bioactivity. FGF9-loaded and unloaded electrospun fibers were found to support the proliferation of fibroblasts for five days even in serum-depleted conditions. Cells cultured on FGF9-supplemented PEA mats resulted in upregulation of PDGFRβ in concentration and cell type-dependent manner.

Conclusion

This study supports the premise of controlled delivery of FGF9 from PEA electrospun fibers for potential therapeutic angiogenesis applications.

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Dragneva G, Korpisalo P, Yla-Herttuala S. Promoting Blood Vessel Growth in Ischemic Diseases: Challenges in Translating Preclinical Potential into Clinical Success. Dis Model Mech. 2013;6(2):312–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Lee KY, Peters MC, Mooney DJ. Comparison of Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor on Angiogenesis in SCID Mice. J Control Release. 2003;87(1–3):49–56.

    Article  CAS  PubMed  Google Scholar 

  4. Said SS, Pickering JG, Mequanint K. Advances in Growth Factor Delivery for Therapeutic Angiogenesis. J Vasc Res. 2013;50(1):35–51.

    Article  CAS  PubMed  Google Scholar 

  5. Sahoo S, Ang LT, Goh JC-H, Toh SL. Growth Factor Delivery Through Electrospun Nanofibers in Scaffolds for Tissue Engineering Applications. J Biomed Mater Res. 2010;93A:1539–50.

    CAS  Google Scholar 

  6. Yang Y, Xia T, Zhi W, Wei L, Weng J, Zhang C, et al. Promotion of Skin Regeneration in Diabetic Rats by Electrospun Core-Sheath Fibers Loaded With Basic Fibroblast Growth Factor. Biomaterials. 2011;32(18):4243–54.

    Article  CAS  PubMed  Google Scholar 

  7. Seyednejad H, Ji W, Yang F, van Nostrum CF, Vermonden T, van den Beucken JJ, et al. Coaxially Electrospun Scaffolds Based on Hydroxyl-Functionalized Poly (Epsilon-Caprolactone) and Loaded With VEGF for Tissue Engineering Applications. Biomacromolecules. 2012;13(11):3650–60.

    Article  CAS  PubMed  Google Scholar 

  8. Roy RS, Roy B, Sengupta S. Emerging Technologies for Enabling Proangiogenic Therapy. Nanotechnology. 2011;22(49):494004.

    Article  PubMed  Google Scholar 

  9. Rubanyi GM. Angiogenesis in health and disease: Basic mechanisms and clinical applications. New york: Marcel Dekker Inc.; 2000.

  10. Agrotis A, Kanellakis P, Kostolias G, Di Vitto G, Wei C, Hannan R, et al. Proliferation of Neointimal Smooth Muscle Cells After Arterial Injury. Dependence on Interactions Between Fibroblast Growth Factor Receptor-2 and Fibroblast Growth Factor-9. J Biol Chem. 2004;279(40):42221–9.

    Article  CAS  PubMed  Google Scholar 

  11. Spicer D. FGF9 on the Move. Nat Genet. 2009;41(3):272–3.

    Article  CAS  PubMed  Google Scholar 

  12. Frontini MJ, Nong Z, Gros R, Drangova M, O’Neil C, Rahman MN, et al. Fibroblast Growth Factor 9 Delivery During Angiogenesis Produces Durable, Vasoresponsive Microvessels Wrapped by Smooth Muscle Cells. Nat Biotechnol. 2011;29(5):421–7.

    Article  CAS  PubMed  Google Scholar 

  13. Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric System for Dual Growth Factor Delivery. Nat Biotechnol. 2001;19(11):1029–34.

    Article  CAS  PubMed  Google Scholar 

  14. Knight DK, Gillies ER, Mequanint K. Strategies in Functional Poly (ester amide) Syntheses to Study Human Coronary Artery Smooth Muscle Cell Interactions. Biomacromolecules. 2011;12(7):2475–87.

    Article  CAS  PubMed  Google Scholar 

  15. Vert M, Li S, Garreau H. New Insights on the Degradation of Bioresorbable Polymeric Devices Based on Lactic and Glycolic Acids. Clin Mater. 1992;10(1–2):3–8.

    Article  CAS  PubMed  Google Scholar 

  16. Szentivanyi A, Chakradeo T, Zernetsch H, Glasmacher B. Electrospun Cellular Microenvironments: Understanding Controlled Release and Scaffold Structure. Adv Drug Delivery Rev. 2011;63(4–5):209–20.

    Article  CAS  Google Scholar 

  17. Li L, Chu CC. Nitroxyl Radical Incorporated Electrospun Biodegradable Poly (Ester Amide) Nanofiber Membranes. J Biomater Sci Polym Ed. 2009;20(3):341–61.

    Article  CAS  PubMed  Google Scholar 

  18. Srinath D, Lin S, Knight DK, Rizkalla AS, Mequanint K. Fibrous Biodegradable L-alanine-based Scaffolds for Vascular Tissue Engineering. J Tissue Eng Regen Med. 2012.

  19. Valle L, Roa M, Diaz A, Casas M, Puiggali J, Rodriguez-Galan A. Electrospun Nanofibers of a Degradable Poly (Ester amide). Scaffolds Loaded with Antimicrobial Agents. J Polym Res. 2012;19(2):1–13.

  20. Morgan PW. Interfacial Polymerization. Encyclopedia of Polymer Science and Technology: John Wiley & Sons, Inc.; 2002.

  21. Pham QP, Sharma U, Mikos AG. Electrospinning of Polymeric Nanofibers for Tissue Engineering Applications: A Review. Tissue Eng. 2006;12(5):1197–211.

    Article  CAS  PubMed  Google Scholar 

  22. Zong X, Kim K, Fang D, Ran S, Hsiao BS, Chu B. Structure and Process Relationship of Electrospun Bioabsorbable Nanofiber Membranes. Polymer. 2002;43(16):4403–12.

    Article  CAS  Google Scholar 

  23. Jarusuwannapoom T, Hongrojjanawiwat W, Jitjaicham S, Wannatong L, Nithitanakul M, Pattamaprom C, et al. Effect of Solvents on Electro-Spinnability of Polystyrene Solutions and Morphological Appearance of Resulting Electrospun Polystyrene Fibers. Eur Polym J. 2005;41(3):409–21.

    Article  CAS  Google Scholar 

  24. Tsitlanadze G, Machaidze M, Kviria T, Djavakhishvili N, Chu CC, Katsarava R. Biodegradation of Amino-Acid-Based Poly (Ester Amide)s: In Vitro Weight Loss and Preliminary in Vivo Studies. J Biomater Sci Polym Ed. 2004;15(1):1–24.

    Article  CAS  PubMed  Google Scholar 

  25. Zamani M, Morshed M, Varshosaz J, Jannesari M. Controlled Release of Metronidazole Benzoate from Poly Epsilon-Caprolactone Electrospun Nanofibers for Periodontal Diseases. Eur J Pharm Biopharm. 2010;75(2):179–85.

    Article  CAS  PubMed  Google Scholar 

  26. Zeng J, Yang L, Liang Q, Zhang X, Guan H, Xu X, et al. Influence of the Drug Compatibility With Polymer Solution on the Release Kinetics of Electrospun Fiber Formulation. J Control Release. 2005;105(1–2):43–51.

    Article  CAS  PubMed  Google Scholar 

  27. Maretschek S, Greiner A, Kissel T. Electrospun Biodegradable Nanofiber Nonwovens for Controlled Release of Proteins. J Control Release. 2008;127(2):180–7.

    Article  CAS  PubMed  Google Scholar 

  28. Sy JC, Klemm AS, Shastri VP. Emulsion as a Means of Controlling Electrospinning of Polymers. Adv Mater. 2009;21(18):1814–9.

    Article  CAS  Google Scholar 

  29. Yang Y, Li X, He S, Cheng L, Chen F, Zhou S, et al. Biodegradable Ultrafine Fibers With Core–Sheath Structures for Protein Delivery and its Optimization. Polym Adv Technol. 2011;22(12):1842–50.

    Article  CAS  Google Scholar 

  30. Ritger PL, Peppas NA. A Simple Equation for Description of Solute Release I. Fickian and non-Fickian Release from non-Swellable Devices in the Form of Slabs, Spheres, Cylinders or Discs. J Control Release. 1986;5(1):23–36.

    Article  Google Scholar 

  31. Baker SC, Southgate J. Towards Control of Smooth Muscle Cell Differentiation in Synthetic 3D Scaffolds. Biomaterials. 2008;29(23):3357–66.

    Article  CAS  PubMed  Google Scholar 

  32. Naruo K, Seko C, Kuroshima K, Matsutani E, Sasada R, Kondo T, et al. Novel Secretory Heparin-Binding Factors from Human Glioma Cells (Glia-Activating Factors) Involved in Glial Cell Growth. Purification and Biological Properties. J Biol Chem. 1993;268(4):2857–64.

    CAS  PubMed  Google Scholar 

  33. Rubin JS, Chan AM, Bottaro DP, Burgess WH, Taylor WG, Cech AC, et al. A Broad-Spectrum Human Lung Fibroblast-Derived Mitogen is a Variant of Hepatocyte Growth Factor. Proc Natl Acad Sci. 1991;88(2):415–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Richardson WJ, Wilson E, Moore Jr JE. Altered Phenotypic Gene Expression of 10T1/2 Mesenchymal Cells in Nonuniformly Stretched PEGDA Hydrogels. Am J Physiol Cell Physiol. 2013;305(1):C100–110.

  35. Horwitz JA, Shum KM, Bodle JC, Deng M, Chu CC, Reinhart-King CA. Biological Performance of Biodegradable Amino Acid-Based Poly (Ester Amide)s: Endothelial Cell Adhesion and Inflammation In Vitro. J Biomed Mater Res A. 2010;95(2):371–80.

    Article  PubMed  Google Scholar 

  36. Deng M, Wu J, Reinhart-King CA, Chu CC. Biodegradable Functional Poly (Ester Amide)s With Pendant Hydroxyl Functional Groups: Synthesis, Characterization, Fabrication and In Vitro Cellular Response. Acta Biomater. 2011;7(4):1504–15.

    Article  CAS  PubMed  Google Scholar 

  37. Lin S, Sandig M, Mequanint K. Three-Dimensional Topography of Synthetic Scaffolds Induces Elastin Synthesis by Human Coronary Artery Smooth Muscle Cells. Tissue Eng Part A. 2011;17(11–12):1561–71.

    Article  CAS  PubMed  Google Scholar 

  38. Carlson AL, Florek CA, Kim JJ, Neubauer T, Moore JC, Cohen RI, et al. Microfibrous Substrate Geometry as a Critical Trigger for Organization, Self-Renewal, and Differentiation of Human Embryonic Stem Cells Within Synthetic 3-Dimensional Microenvironments. Faseb J. 2012;26(8):3240–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Zhou L, Takayama Y, Boucher P, Tallquist MD, Herz J. LRP1 Regulates Architecture of the Vascular Wall by Controlling PDGFRÎ2-Dependent Phosphatidylinositol 3-Kinase Activation. PLoS One. 2009;4(9):e6922.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-Beta in Recruitment of Vascular Smooth Muscle Cells and Pericytes During Embryonic Blood Vessel Formation in the Mouse. Development. 1999;126(14):3047–55.

    CAS  PubMed  Google Scholar 

  41. Zhang H, Jia X, Han F, Zhao J, Zhao Y, Fan Y, et al. Dual-Delivery of VEGF and PDGF by Double-Layered Electrospun Membranes for Blood Vessel Regeneration. Biomaterials. 2012;34(9):2202–12.

    Article  Google Scholar 

Download references

Acknowledgments and Disclosures

The Authors acknowledge the financial support from The Heart and Stroke Foundation of Canada (T-7262), the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes for Health Research (FRN 11715), and the Canadian Cancer Society (Grant #701080). S. S. Said held a CIHR Strategic Training Fellowship in Vascular Research (2011–2013). J. G. Pickering holds the Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair. Thanks to D. K. Knight for his assistance in the synthesis of PEA and performing the GPC molecular weight analysis.

Author information

Authors and Affiliations

  1. Biomedical Engineering Graduate Program, The University of Western Ontario, London, Ontario, Canada

    Somiraa S. Said

  2. Department of Medicine (Cardiology), Department of Biochemistry, and Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada

    J. Geoffrey Pickering

  3. Department of Chemical and Biochemical Engineering and Biomedical Engineering Graduate Program, The University of Western Ontario, 1151 Richmond Street, London, Ontario, N6A 5B9, Canada

    Kibret Mequanint

Authors
  1. Somiraa S. Said
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Geoffrey Pickering
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kibret Mequanint
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kibret Mequanint.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Said, S.S., Pickering, J.G. & Mequanint, K. Controlled Delivery of Fibroblast Growth Factor-9 from Biodegradable Poly(ester amide) Fibers for Building Functional Neovasculature. Pharm Res 31, 3335–3347 (2014). https://doi.org/10.1007/s11095-014-1423-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1423-2

Key Words

Search

Navigation