Poly(vinyl alcohol co-vinyl acetate) as a novel scaffold for mammalian cell culture and controlled drug release

  • Francisca Villanueva-Flores
  • Margarita Miranda-Hernández
  • José O. Flores-Flores
  • Alberto Porras-Sanjuanico
  • Hailin Hu
  • Leonor Pérez-Martínez
  • Octavio T. Ramírez
  • Laura A. PalomaresEmail author
Materials for life sciences


Tissue engineering requires novel smart materials to sustain cell growth, tissue regeneration and in situ drug release in a controlled mode. Also, biocompatible synthesis methods are needed to immobilize biologically active compounds. Poly(vinyl alcohol co-vinyl acetate) (PAcVA) was synthesized at 37 °C using glutaraldehyde (GA) as a crosslinking agent. The mechanical characteristics of the polymer were manipulated by varying crosslinking degrees using different GA concentrations. Materials with Young’s modules similar to soft tissues, adequate for tissue engineering, were obtained. PAcVA was a pH-responsive material with maximum swelling at pH 5.8. When hydrated, PAcVA was electro-responsive. Fluorescein was used as a model molecule to characterize the releasing properties of the polymer. Effective diffusivities were a function of the crosslinking degree. Release rates were proportional to temperature and were faster at lower GA contents. According to a fit to the Korsmeyer–Peppas’ model, diffusion at 5 and 10% GA was Fickian, but at 20% GA, diffusion was abnormal. To promote cell attachment and neutralize free aldehyde groups, PAcVA hydrogels were covered with poly-l-lysine and laminin, which supported growth of lung carcinoma and mouse hypothalamic cells without signs of cytotoxicity or oxidative stress. An intelligent low-cost hydrogel with properties that can be easily modulated was synthesized and fully characterized. Its properties make it suitable for tissue engineering applications, as they mimic the mechanical properties of natural tissues.



Research performed thanks to the financial support of the Programa UNAM-DGAPA-PAPIIT IT-200416. F. Villanueva received a scholarship from CONACyT during her graduate studies. We thank Mariana Ramírez Gilly (Facultad de Química UNAM), Melina Tapia Tapia (Instituto de Química UNAM), Manuel Aguilar Franco (Laboratorio Central de Microscopía UNAM), Martha A. Contreras, Ruth Pastor, Vanessa Hernández, Guadalupe Zavala Padilla, Arturo Pimentel Cabrera and the National Laboratory of Advanced Microscopy (LNMA-IBT-UNAM) for technical support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10853_2019_3402_MOESM1_ESM.docx (18 kb)
Supplementary information (S): File S1. Detailed procedure to obtain Eq. 6, used to determine effective diffusivities of fluorescein across PAcVA films (DOCX 18 kb)


  1. 1.
    Zhu J, Marchant RE (2011) Design properties of hydrogel tissue-engineering scaffolds. Exp Rev Med Dev 8:607–626. CrossRefGoogle Scholar
  2. 2.
    El-Sherbiny I, Yacoub M (2013) Hydrogel scaffolds for tissue engineering: progress and challenges. Glob Cardiol Sci Pract 2013:316–342. Google Scholar
  3. 3.
    Kohane DS, Langer R (2008) Polymeric biomaterials in tissue engineering. Pediatr Res 63:487–491. CrossRefGoogle Scholar
  4. 4.
    Balint R, Cassidy NJ, Cartmell SH (2014) Conductive polymers: towards a smart biomaterial for tissue engineering. Acta Biomater 10:2341–2353. CrossRefGoogle Scholar
  5. 5.
    Khan F, Tanaka M (2017) Designing smart biomaterials for tissue engineering. Int J Mol Sci 19:17. CrossRefGoogle Scholar
  6. 6.
    Furth ME, Atala A, Van Dyke ME (2007) Smart biomaterials design for tissue engineering and regenerative medicine. Biomaterials 28:5068–5073. CrossRefGoogle Scholar
  7. 7.
    Kumar A, Han SS (2017) PVA-based hydrogels for tissue engineering: a review. Int J Polym Mater Polym Biomater 66:159–182. CrossRefGoogle Scholar
  8. 8.
    Rudra R, Kumar V, Kundu PP (2015) Acid catalysed cross-linking of poly vinyl alcohol (PVA) by glutaraldehyde: effect of crosslink density on the characteristics of PVA membranes used in single chambered microbial fuel cells. RSC Adv 5:83436–83447. CrossRefGoogle Scholar
  9. 9.
    Figueiredo KCS, Alves TLM, Borges CP (2009) Poly(vinyl alcohol) Films crosslinked by glutaraldehyde under mild conditions. J Appl Polym Sci 111:3074–3080. CrossRefGoogle Scholar
  10. 10.
    Mansur HS, Sadahira CM, Souza AN, Mansur AAP (2008) FTIR spectroscopy characterization of poly (vinyl alcohol) hydrogel with different hydrolysis degree and chemically crosslinked with glutaraldehyde. Mater Sci Eng, C 28:539–548. CrossRefGoogle Scholar
  11. 11.
    Fumio U, Hiroshi Y, Kumiko N et al (1990) Swelling and mechanical properties of poly(vinyl alcohol) hydrogels. Int J Pharm 58:135–142. CrossRefGoogle Scholar
  12. 12.
    Gohil JM, Bhattacharya A, Ray P (2006) Studies on the crosslinking of poly(vinyl alcohol). J Polym Res 13:161–169. CrossRefGoogle Scholar
  13. 13.
    Zhang Y, Zhu PC, Edgren D (2010) Crosslinking reaction of poly(vinyl alcohol) with glyoxal. J Polym Res 17:725–730. CrossRefGoogle Scholar
  14. 14.
    Teramoto N, Saitoh M, Kuroiwa J et al (2001) Morphology and mechanical properties of pullulan/poly(vinyl alcohol) blends crosslinked with glyoxal. J Appl Polym Sci 82:2273–2280. CrossRefGoogle Scholar
  15. 15.
    Chen CT, Chang YJ, Chen MC, Tobolsky AV (1973) Formalized poly(vinyl alcohol) membranes for reverse osmosis. J Appl Polym Sci 17:789–796. CrossRefGoogle Scholar
  16. 16.
    Jian S, Xiao Ming S (1987) Crosslinked PVA-PS thin-film composite membrane for reverse osmosis. Desalination 62:395–403. CrossRefGoogle Scholar
  17. 17.
    Burshe MC, Sawant SB, Joshi JB, Pangarkar VG (1997) Sorption and permeation of binary water-alcohol systems through PVA membranes crosslinked with multifunctional crosslinking agents. Sep Purif Technol 12:145–156. CrossRefGoogle Scholar
  18. 18.
    Araujo AM, Neves MT Jr, Azevedo WM et al (1997) Polyvinyl alcohol-glutaraldehyde network as a support for protein immobilisation. Biotechnol Tech 11:67–70CrossRefGoogle Scholar
  19. 19.
    Migneault I, Dartiguenave C, Bertrand MJ, Waldron KC (2004) Glutaraldehyde: behavior in aqueous solution, reaction with proteins, and application to enzyme crosslinking. Biotechniques 37:790–796CrossRefGoogle Scholar
  20. 20.
    Kim KJ, Lee SB, Han NW (1994) Kinetics of crosslinking reaction of PVA membrane with glutaraldehyde. Korean J Chem Eng 11:41–47. CrossRefGoogle Scholar
  21. 21.
    Hassan CM, Peppas NA (2000) Structure and applications of poly(vinyl alcohol) hydrogels produced by conventional crosslinking or by freezing/thawing methods. In: BT—biopolymers · PVA hydrogels, anionic polymerisation nanocomposites. Springer, Berlin, pp 37–65Google Scholar
  22. 22.
    Antonietti M, Caruso RA, Göltner CG, Weissenberger MC (1999) Morphology variation of porous polymer gels by polymerization in lyotropic surfactant phases. Macromolecules 32:1383–1389. CrossRefGoogle Scholar
  23. 23.
    Ahearne M, Yang Y, El Haj AJ et al (2005) Characterizing the viscoelastic properties of thin hydrogel-based constructs for tissue engineering applications. J R Soc Interface 2:455–463. CrossRefGoogle Scholar
  24. 24.
    Liebschner M, Bucklen B, Wettergreen M (2005) Mechanical aspects of tissue engineering. Semin Plast Surg 19:217–228. CrossRefGoogle Scholar
  25. 25.
    Xia T, Liu W, Yang L (2017) A review of gradient stiffness hydrogels used in tissue engineering and regenerative medicine. J Biomed Mater Res, Part A 105:1799–1812. CrossRefGoogle Scholar
  26. 26.
    Bas O, Catelas I, De-Juan-Pardo EM, Hutmacher DW (2018) The quest for mechanically and biologically functional soft biomaterials via soft network composites. Adv Drug Deliv Rev 132:214–234. CrossRefGoogle Scholar
  27. 27.
    Sonker AK, Rathore K, Nagarale RK, Verma V (2018) Crosslinking of polyvinyl alcohol (PVA) and effect of crosslinker shape (aliphatic and aromatic) thereof. J Polym Environ 26:1782–1794. CrossRefGoogle Scholar
  28. 28.
    Peng Z, Li Z, Zhang F, Peng X (2012) Preparation and properties of polyvinyl alcohol/collagen hydrogel. J Macromol Sci Part B 51:1934–1941. CrossRefGoogle Scholar
  29. 29.
    Liang XLX, Boppart SA (2010) Biomechanical properties of in vivo human skin from dynamic optical coherence elastography. IEEE Trans Biomed Eng 57:953–959. CrossRefGoogle Scholar
  30. 30.
    van Dommelen JAW, van der Sande TPJ, Hrapko M, Peters GWM (2010) Mechanical properties of brain tissue by indentation: Interregional variation. J Mech Behav Biomed Mater 3:158–166. CrossRefGoogle Scholar
  31. 31.
    Soza G, Grosso R, Nimsky C et al (2005) Determination of the elasticity parameters of brain tissue with combined simulation and registration. Int J Med Robot 1:87–95. CrossRefGoogle Scholar
  32. 32.
    Wadhwa R, Lagenaur CF, Cui XT (2006) Electrochemically controlled release of dexamethasone from conducting polymer polypyrrole coated electrode. J Control Release 110:531–541. CrossRefGoogle Scholar
  33. 33.
    Kato Y, Ozawa S, Miyamoto C et al (2013) Acidic extracellular microenvironment and cancer. Cancer Cell Int 13:89. CrossRefGoogle Scholar
  34. 34.
    Muthukumar M, Edwards SF (1982) Screening concepts in polymer solution dynamics. Polymer (Guildf) 23:345–348. CrossRefGoogle Scholar
  35. 35.
    Rusling JF, Suib SL (1994) Characterizing materials with cyclic voltammetry. Adv Mater 6:922–930. CrossRefGoogle Scholar
  36. 36.
    Daubinger P, Kieninger J, Unmüssig T, Urban G (2014) Electrochemical characteristics of nanostructured platinum electrodes—a cyclic voltammetry study. Phys Chem Chem Phys 16:8392–8399CrossRefGoogle Scholar
  37. 37.
    Hille B (2001) Ion channel excitable membranes, 3rd edn. Sinauer Associates Inc, Sunderland, MA, pp 1–37Google Scholar
  38. 38.
    Mawad D, Odell R, Poole-Warren LA (2009) Network structure and macromolecular drug release from poly(vinyl alcohol) hydrogels fabricated via two crosslinking strategies. Int J Pharm 366:31–37. CrossRefGoogle Scholar
  39. 39.
    Renkin EM (1954) Filtration, diffusion and molecular sieving through porous cellulose membranes. J Gen Physiol 38:225–243Google Scholar
  40. 40.
    Dash S, Murthy PN, Nath L, Chowdhury P (2010) Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm 67:217–223Google Scholar
  41. 41.
    Siepmann J, Siepmann F (2008) Mathematical modeling of drug delivery. Int J Pharm 364:328–343. CrossRefGoogle Scholar
  42. 42.
    Higuchi T (1963) Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 52:1145–1149. CrossRefGoogle Scholar
  43. 43.
    Korsmeyer RW, Gurny R, Doelker E et al (1983) Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 15:25–35. CrossRefGoogle Scholar
  44. 44.
    Shamaeli E, Alizadeh N (2014) Nanostructured biocompatible thermal/electrical stimuli-responsive biopolymer-doped polypyrrole for controlled release of chlorpromazine: kinetics studies. Int J Pharm 472:327–338. CrossRefGoogle Scholar
  45. 45.
    Ritger PL, Peppas NA (1987) 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 5:23–36. CrossRefGoogle Scholar
  46. 46.
    Varshosaz J, Hajian M (2004) Characterization of drug release and diffusion mechanism through hydroxyethylmethacrylate/methacrylic acid pH-sensitive hydrogel. Drug Deliv 11:53–58. CrossRefGoogle Scholar
  47. 47.
    LoPachin RM, Gavin T (2014) Molecular mechanisms of aldehyde toxicity: a chemical perspective. Chem Res Toxicol 27:1081–1091. CrossRefGoogle Scholar
  48. 48.
    Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81–128. CrossRefGoogle Scholar
  49. 49.
    Kehrer JP, Biswal SS (2000) The molecular effects of acrolein. Toxicol Sci 57:6–15CrossRefGoogle Scholar
  50. 50.
    Gough JE, Scotchford CA, Downes S (2002) Cytotoxicity of glutaraldehyde crosslinked collagen/poly(vinyl alcohol) films is by the mechanism of apoptosis. J Biomed Mater Res 61:121–130. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Instituto de BiotecnologíaUniversidad Nacional Autónoma de MéxicoCuernavacaMexico
  2. 2.Instituto de Energías RenovablesUniversidad Nacional Autónoma de MéxicoTemixcoMexico
  3. 3.Instituto de Ciencias Aplicadas y TecnologíaUniversidad Nacional Autónoma de MéxicoCiudad de MéxicoMexico

Personalised recommendations