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.

  • Original Article
  • Published:

Lysine-oligoether-modified electrospun poly(carbonate urethane) matrices for improving hemocompatibility response

Polymer Journal volume 53, pages 1393–1402 (2021)Cite this article

Subjects

Abstract

Although biomedical devices have greatly evolved, none of the materials that have been used to date are able to meet all the hemocompatibility criteria. The rapid accumulation of proteins at the implant surface and the subsequent physiological response are the main causes of failure. Thus, the appropriate design of antithrombotic materials is of the utmost importance. In this work, we employed Carbothane® electrospun matrices (PCU) for lysine surface modification, using oligomers obtained from allyl glycidyl ether (AGE) reaction as spacers. This technique enables the binding of several lysine molecules per urethane linkage, which, along with the large surface-to-volume ratio of the electrospun membranes, leads to high ε-amino free lysine grafting (29 ± 2 nmol cm−2). The incorporation of AGE oligomers significantly reduced the nonspecific protein adsorption, while further modification with lysine led to a more pronounced decrease (25% for BSA, 35% for fibrinogen, and 30% for PNP proteins, with respect to PCU membranes). The lysine-modified matrices presented increased plasminogen adsorption capacity and in vitro clot lysis ability after incubation in pooled normal human plasma and tissue plasminogen activator, confirming the plasminogen adsorption selectivity and thus improving the hemocompatibility behavior of these matrices. Therefore, the obtained electrospun membranes are promising coatings for biomedical devices with fibrinolytic activity.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mc Namara K, Alzubaidi H, Jackson JK. Cardiovascular disease as a leading cause of death: how are pharmacists getting involved? Integr Pharm Res Pract. 2019;8:1–11. https://doi.org/10.2147/iprp.s133088.

    Article  Google Scholar 

  2. Fischer M, Maitz MF, Werner C Coatings for biomaterials to improve hemocompatibility. In: Siedlecki CA, ed. Hemocompatibility of biomaterials for clinical applications: blood-biomaterials interactions. Cambridge: Woodhead Publishing; 2018:163−90.

  3. Williams DF. There is no such thing as a biocompatible material. Biomaterials. 2014;35:10009–14. https://doi.org/10.1016/j.biomaterials.2014.08.035.

    Article  CAS  PubMed  Google Scholar 

  4. Chen H, Yuan L, Song W, Wu Z, Li D. Biocompatible polymer materials: role of protein-surface interactions. Prog Polym Sci (Oxf). 2008;33:1059–87. https://doi.org/10.1016/j.progpolymsci.2008.07.006.

    Article  CAS  Google Scholar 

  5. Jaffer IH, Fredenburgh JC, Hirsh J, Weitz JI. Medical device-induced thrombosis: what causes it and how can we prevent it? J Thrombosis Haemost. 2015;13:S72–S81. https://doi.org/10.1111/jth.12961.

    Article  Google Scholar 

  6. Ratner BD, Hoffman AS, Schoen FJ, Lemons JE. Biomaterials science: an introduction to materials in medicine. 3rd ed. New York, NY: Academic Press.; 2013.

  7. Zdrahala RJ, Zdrahala IJ. Biomedical applications of polyurethanes: a review of past promises, present realities, and a vibrant future. J Biomater Appl. 1999;14:67–90. https://doi.org/10.1177/088532829901400104.

    Article  CAS  PubMed  Google Scholar 

  8. De Bartolo L, Morelli S, Piscioneri A, Lopez LC, Favia P, d’Agostino R, et al. Novel membranes and surface modification able to activate specific cellular responses. Biomolecular Eng. 2007;24:23–26. https://doi.org/10.1016/j.bioeng.2006.07.001. 1 SPEC. ISS.

    Article  CAS  Google Scholar 

  9. Solouk A, Solati-Hashjin M, Najarian S, Mirzadeh H, Seifalian AM. Optimization of acrylic acid grafting onto POSS-PCU nanocomposite using response surface methodology. Iran Polym J. 2011;20:91–107.

    CAS  Google Scholar 

  10. Caracciolo PC, Rial-Hermida MI, Montini-Ballarin F, Abraham GA, Concheiro A, Alvarez-Lorenzo C. Surface-modified bioresorbable electrospun scaffolds for improving hemocompatibility of vascular grafts. Mater Sci Eng C. 2017;75:1115–27. https://doi.org/10.1016/j.msec.2017.02.151.

    Article  CAS  Google Scholar 

  11. Abraham GA, De Queiroz AAA, Román JS. Immobilization of a nonsteroidal antiinflammatory drug onto commercial segmented polyurethane surface to improve haemocompatibility properties. Biomaterials. 2002;23:1625–38. https://doi.org/10.1016/S0142-9612(01)00289-7.

    Article  CAS  PubMed  Google Scholar 

  12. Guan YQ, Zheng Z, Li Z, Liu JM. Cell death in HeLa mediated by thermoplastic polyurethane with co-immobilized IFN-γ plus TNF-α. Acta Biomaterialia. 2012;8:1348–56. https://doi.org/10.1016/j.actbio.2011.11.023.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang J, Yang B, Jia Q, Xiao M, Hou Z. Preparation, physicochemical properties, and hemocompatibility of the composites based on biodegradable poly(ether-ester-urethane) and phosphorylcholine-containing copolymer. Polymers. 2019;11:860 https://doi.org/10.3390/polym11050860.

    Article  CAS  PubMed Central  Google Scholar 

  14. Hou Z, Xu J, Teng J, Jia Q, Wang X. Facile preparation of medical segmented poly(ester-urethane) containing uniformly sized hard segments and phosphorylcholine groups for improved hemocompatibility. Mater Sci Eng C 2020;109:110571 https://doi.org/10.1016/j.msec.2019.110571.

    Article  CAS  Google Scholar 

  15. Ontaneda A, Annich GM. Novel surfaces in extracorporeal membrane oxygenation circuits. Front Med. 2018;5(NOV):321.

    Article  Google Scholar 

  16. Park KD, Okano T, Nojiri C, Kim SW. Polyurethaneurea surfaces - effect of hydrophilic spacers. J Biomed Mater Res. 1988;22:977–92.

    Article  CAS  PubMed  Google Scholar 

  17. Chen H, Zhang Y, Li D, Hu X, Wang L, McClung WG, et al. Surfaces having dual fibrinolytic and protein resistant properties by immobilization of lysine on polyurethane through a PEG spacer. J Biomed Mater Res. 2009;90:940–6. https://doi.org/10.1002/jbm.a.32152.

    Article  CAS  Google Scholar 

  18. Gu H, Chen X, Yu Q, Liu X, Zhan W, Chen H, et al. A multifunctional surface for blood contact with fibrinolytic activity, ability to promote endothelial cell adhesion and inhibit smooth muscle cell adhesion. J Mater Chem B. 2017;5:604–11. https://doi.org/10.1039/c6tb02808j.

    Article  CAS  PubMed  Google Scholar 

  19. Li D, Chen H, Glenn McClung W, Brash JL. Lysine-PEG-modified polyurethane as a fibrinolytic surface: Effect of PEG chain length on protein interactions, platelet interactions and clot lysis. Acta Biomaterialia. 2009;5:1864–71. https://doi.org/10.1016/j.actbio.2009.03.001.

    Article  CAS  PubMed  Google Scholar 

  20. Wu Z, Chen H, Li D, Brash JL. Tissue plasminogen activator-containing polyurethane surfaces for fibrinolytic activity. Acta Biomaterialia. 2011;7:1993–8. https://doi.org/10.1016/j.actbio.2011.01.026.

    Article  CAS  PubMed  Google Scholar 

  21. Li D, Chen H, Wang S, Wu Z, Brash JL. Lysine–poly(2-hydroxyethyl methacrylate) modified polyurethane surface with high lysine density and fibrinolytic activity. Acta Biomaterialia. 2011;7:954–8. https://doi.org/10.1016/j.actbio.2010.10.021.

    Article  CAS  PubMed  Google Scholar 

  22. Anglés-Cano E. Overview on fibrinolysis: plasminogen activation pathways on fibrin and cell surfaces. Chem Phys Lipids. 1994;67–68:353–62. https://doi.org/10.1016/0009-3084(94)90157-0.

    Article  PubMed  Google Scholar 

  23. Klement P, Du YJ, Berry L, Andrew M, Chan AKC. Blood-compatible biomaterials by surface coating with a novel antithrombin-heparin covalent complex. Biomaterials. 2002;23:527–35. https://doi.org/10.1016/S0142-9612(01)00135-1.

    Article  CAS  PubMed  Google Scholar 

  24. Sheppeck IIJE, Kar H, Hong H. A convenient and scaleable procedure for removing the Fmoc group in solution. Tetrahedron Lett. 2000;41:5329–33.

    Article  CAS  Google Scholar 

  25. Moon JH, Shin JW, Park JW. Self-assembly of aminosilane layers: determination of surface density of the amine group through a reversible chemical reaction. Mol Cryst Liq Cryst Sci Technol Sect A Mol Cryst Liq Cryst. 1997;295:185–8. https://doi.org/10.1080/10587259708042826.

    Article  Google Scholar 

  26. Laemmli UK. Cleavage of structural proteins during the assembly of head of bacteriophage T4. Nat Publ Group. 1970;227:680–5.

    CAS  Google Scholar 

  27. Schneider CA, Rasband WS, Eliceiri KW. NIH image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–75. https://doi.org/10.1038/nmeth.2089. Accessed 9 July 2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. R Core Team. R: A language and environment for statistical computing. 2019.

  29. Meng F, Qiao Z, Yao Y, Luo J. Synthesis of polyurethanes with pendant azide groups attached on the soft segments and the surface modification with mPEG by click chemistry for antifouling applications. RSC Adv. 2018;8:19642–50. https://doi.org/10.1039/c8ra02912a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xie D, Howard L, Almousa R. Surface modification of polyurethane with a hydrophilic, antibacterial polymer for improved antifouling and antibacterial function. J Biomater Appl. 2018;33:340–51. https://doi.org/10.1177/0885328218792687.

    Article  CAS  PubMed  Google Scholar 

  31. Feng Y, Tian H, Tan M, Zhang P, Chen Q, Liu J. Surface modification of polycarbonate urethane by covalent linkage of heparin with a PEG spacer. Trans Tianjin Univ. 2013;19:58–65. https://doi.org/10.1007/s12209-013-1894-y.

    Article  CAS  Google Scholar 

  32. Zhou Z, Meyerhoff ME. Preparation and characterization of polymeric coatings with combined nitric oxide release and immobilized active heparin. Biomaterials. 2005;26:6506–17. https://doi.org/10.1016/j.biomaterials.2005.04.046.

    Article  CAS  PubMed  Google Scholar 

  33. Joung YK, Hwang IK, Park KD, Lee CW. CD34 monoclonal antibody-immobilized electrospun polyurethane for the endothelialization of vascular grafts. Macromol Res. 2010;18:904–12. https://doi.org/10.1007/s13233-010-0908-z.

    Article  CAS  Google Scholar 

  34. Lin H‐B, Sun W, Mosher DF, García-Echeverría C, Schaufelberger K, Lelkes PI, et al. Synthesis, surface, and cell‐adhesion properties of polyurethanes containing covalently grafted RGD‐peptides. J Biomed Mater Res. 1994;28:329–42. https://doi.org/10.1002/jbm.820280307.

    Article  CAS  PubMed  Google Scholar 

  35. Kang IK, Kwon OH, Kim MK, Lee YM, Sung YK. In vitro blood compatibility of functional group-grafted and heparin-immobilized polyurethanes prepared by plasma glow discharge. Biomaterials. 1997;18:1099–107. https://doi.org/10.1016/S0142-9612(97)00035-5.

    Article  CAS  PubMed  Google Scholar 

  36. Hörl H-H, Nussbaumer D, Wünn E. Process for grafting of nitrogen containing polymers and polymers obtained thereby. Sartorius AG. US5556708, 09/17/1996. https://patentscope.wipo.int/search/en/detail.jsf?docId=US38574050&_fid=WO1991003506.

  37. McClung WG, Clapper DL, Hu SP, Brash JL. Adsorption of plasminogen from human plasma to lysine-containing surfaces. J Biomed Mater Res. 2000;49:409–14. https://doi.org/10.1002/(SICI)1097-4636(20000305)49:3<409::AID-JBM14>3.0.CO;2-0.

    Article  CAS  PubMed  Google Scholar 

  38. Arrua RD, Moya C, Bernardi E, Zarzur J, Strumia M, Igarzabal CIA. Preparation of macroporous monoliths based on epoxy-bearing hydrophilic terpolymers and applied for affinity separations. Eur Polym J. 2010;46:663–72. https://doi.org/10.1016/j.eurpolymj.2010.01.009.

    Article  CAS  Google Scholar 

  39. Fields GB Methods for removing the Fmoc Group. In: Pennington MW, Dunn BM, eds. Methods in molecular biology (Clifton, N.J.), 35. Totowa, NJ: Humana Press; 1994:17–27.

  40. Moon JH, Kim JH, Kim KJ, Kang T-H, Kim B, Kim C-H, et al. Absolute surface density of the amine group of the aminosilylated thin layers: ultraviolet-visible spectroscopy, second harmonic generation, and synchrotron-radiation photoelectron spectroscopy study. Langmuir. 1997;13:4305–10. https://doi.org/10.1021/la9705118.

    Article  CAS  Google Scholar 

  41. Xu H, Luan Y, Wu Z, Li X, Yuan Y, Liu X, et al. Incorporation of lysine-containing copolymer with polyurethane affording biomaterial with specific adsorption of plasminogen. Chin J Chem. 2014;32:44–50. https://doi.org/10.1002/cjoc.201300735.

    Article  CAS  Google Scholar 

  42. McClung WG, Clapper DL, Hu SP, Brash JL. Lysine-derivatized polyurethane as a clot lysing surface: conversion of adsorbed plasminogen to plasmin and clot lysis in vitro. Biomaterials. 2001;22:1919–24. https://doi.org/10.1016/S0142-9612(00)00378-1.

    Article  CAS  PubMed  Google Scholar 

  43. Tang Z, Liu X, Luan Y, Liu W, Wu Z, Li D, et al. Regulation of fibrinolytic protein adsorption on polyurethane surfaces by modification with lysine-containing copolymers. Polym Chem. 2013;4:5597–602. https://doi.org/10.1039/c3py00710c.

    Article  CAS  Google Scholar 

  44. Yang W, Tang Z, Luan Y, Liu W, Li D, Chen H. Thermoresponsive copolymer decorated surface enables controlling the adsorption of a target protein in plasma. ACS Appl Mater Interfaces. 2014;6:10146–52. https://doi.org/10.1021/am501193b.

    Article  CAS  PubMed  Google Scholar 

  45. Wang H, Feng Y, Fang Z, Yuan W, Khan M. Co-electrospun blends of PU and PEG as potential biocompatible scaffolds for small-diameter vascular tissue engineering. Mater Sci Eng C. 2012;32:2306–15. https://doi.org/10.1016/j.msec.2012.07.001.

    Article  CAS  Google Scholar 

  46. Luan Y, Li D, Wei T, Wang M, Tang Z, Brash JL, et al. “Hearing Loss” in QCM measurement of protein adsorption to protein resistant polymer brush layers. Anal Chem. 2017;89:4184–91. https://doi.org/10.1021/acs.analchem.7b00198.

    Article  CAS  PubMed  Google Scholar 

  47. Vroman L, Adams AL, Fischer GC, Munoz PC. Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces. Blood. 1980;55:156–9. Accessed 12 Jan 2021 http://www.bloodjournal.org.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Argentinian National Agency of Scientific and Technological Promotion (PICT 2015-153 and PICT 2018–2334 grants), National Research Council (PIP 2017-0153 and PIP 2015-0596 grants) and Universidad Nacional de Mar del Plata (EXA 832/17 and PI2Ba 2020-08 grants). AP thanks the Argentinian National Scientific and Technical Research Council (CONICET) for the postdoctoral fellowship awarded.

Author information

Authors and Affiliations

  1. Instituto de Investigaciones en Ciencia y Tecnología de Materiales, INTEMA (UNMdP-CONICET), Mar del Plata, Argentina

    Alfonso Pepe, Gustavo Abel Abraham & Pablo Christian Caracciolo

  2. Instituto de Investigaciones Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Mar del Plata, Mar del Plata, Argentina

    Maria Gabriela Guevara

Authors
  1. Alfonso Pepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Gabriela Guevara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gustavo Abel Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pablo Christian Caracciolo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pablo Christian Caracciolo.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pepe, A., Guevara, M.G., Abraham, G.A. et al. Lysine-oligoether-modified electrospun poly(carbonate urethane) matrices for improving hemocompatibility response. Polym J 53, 1393–1402 (2021). https://doi.org/10.1038/s41428-021-00534-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41428-021-00534-7

Search

Advanced search

Quick links