, Volume 23, Issue 5, pp 3129–3143 | Cite as

Hemicellulose-reinforced nanocellulose hydrogels for wound healing application

  • Jun Liu
  • Gary Chinga-Carrasco
  • Fang Cheng
  • Wenyang Xu
  • Stefan Willför
  • Kristin SyverudEmail author
  • Chunlin XuEmail author
Original Paper


Polysaccharides are finding an increasing number of applications in medical and pharmaceutical fields thanks to their biodegradability, biocompatibility, and in some cases bioactivity. Two approaches were applied to use hemicelluloses as crosslinkers to tune the structural and mechanical properties of nanofibrillated cellulose (NFC) hydrogel scaffolds, and thus to investigate the effect of these properties on the cellular behavior during wound healing application. Different types of hemicellulose (galactoglucomannan (GGM), xyloglucan (XG), and xylan) were introduced into the NFC network via pre-sorption (Method I) and in situ adsorption (Method II) to reinforce the NFC hydrogels. The charge density of the NFC, the incorporated hemicellulose type and amount, and the swelling time of the hydrogels were found to affect the pore structure, the mechanical strength, and thus the cells’ growth on the composite hydrogel scaffolds. The XG showed the highest adsorption capacity on the NFC, the highest reinforcement effect, and facilitated/promoted cell growth. The pre-sorbed XG in the low-charged NFC network with a lower weight ratio (NFC/XG-90:10) showed the highest efficacy in supporting the growth and proliferation of fibroblast cells (NIH 3T3). These all-polysaccharide composite hydrogels may work as promising scaffolds in wound healing applications to provide supporting networks and to promote cells adhesion, growth, and proliferation.


All-polysaccharide composites Cell behavior Hemicelluloses Hydrogel Mechanical strength Nanofibrillated cellulose Reinforcing Wound healing 



Jun Liu would like to acknowledge the financial support of the China Scholarship Council and Graduate School of Chemical Engineering of Åbo Akademi University. This work is also part of the activities at the Johan Gadolin Process Chemistry Centre, a Centre of Excellence appointed by Åbo Akademi University. NordForsk via the Refining Lignocellulosics to Advanced Polymers and Fibers (PolyRefNorth) network and the NORCEL project (Grant No. 228147) and NanoHeal project (Grant No. 219733), funded by the Research Council of Norway through the NANO2021 Program, are thanked for supporting the research exchange of Jun Liu at PFI. The Research Council of Norway is also acknowledged for the support to the Norwegian Micro- and Nano-Fabrication Facility, NorFab (Grant No. 197411/V30), which facilitated the AFM analysis. Ingebjorg Leirset, Per Olav Johnsen, Anne Reitan, Mirjana Filipovic, Storker Mor, and all other colleagues at PFI are acknowledged for assistance of the laboratory work.

Supplementary material

10570_2016_1038_MOESM1_ESM.doc (12 mb)
Supplementary material 1 (DOC 12,307 kb)


  1. Alexandrescu L, Syverud K, Gatti A, Chinga-Carrasco G (2013) Cytotoxicity tests of cellulose nanofibril-based structures. Cellulose 20:1765–1775. doi: 10.1007/s10570-013-9948-9 CrossRefGoogle Scholar
  2. Andrijevic L, Radotic K, Bogdanovic J, Mutavdzic D, Bogdanovic G (2008) Antiproliferative effect of synthetic lignin against human breast cancer and normal fetal lung cell lines. Potency of low molecular weight fractions. J BUON 13:241–244Google Scholar
  3. Balakrishnan B, Banerjee R (2011) Biopolymer-based hydrogels for cartilage tissue engineering. Chem Rev 111:4453–4474. doi: 10.1021/cr100123h CrossRefGoogle Scholar
  4. Barbucci R (2009) Hydrogels: biological properties and applications. Springer, MilanCrossRefGoogle Scholar
  5. Bhattacharya M et al (2012) Nanofibrillar cellulose hydrogel promotes three-dimensional liver cell culture. J Controll Release 164:291–298. doi: 10.1016/j.jconrel.2012.06.039 CrossRefGoogle Scholar
  6. Bodin A, Ahrenstedt L, Fink H, Brumer H, Risberg B, Gatenholm P (2007) Modification of nanocellulose with a xyloglucan-RGD conjugate enhances adhesion and proliferation of endothelial cells: implications for tissue engineering. Biomacromolecules 8:3697–3704. doi: 10.1021/bm070343q CrossRefGoogle Scholar
  7. Bonilla MR, Lopez-Sanchez P, Gidley MJ, Stokes JR (2015) Micromechanical model of biphasic biomaterials with internal adhesion: application to nanocellulose hydrogel composites. Acta Biomater. doi: 10.1016/j.actbio.2015.10.032 Google Scholar
  8. Borges AC et al (2011) Nanofibrillated cellulose composite hydrogel for the replacement of the nucleus pulposus. Acta Biomater 7:3412–3421. doi: 10.1016/j.actbio.2011.05.029 CrossRefGoogle Scholar
  9. Cartmell SH, Thurstan S, Gittings JP, Griffiths S, Bowen CR, Turner IG (2014) Polarization of porous hydroxyapatite scaffolds: influence on osteoblast cell proliferation and extracellular matrix production. J Biomed Mater Res Part A 102:1047–1052. doi: 10.1002/jbm.a.34790 CrossRefGoogle Scholar
  10. Chang H-I, Wang Y (2011) Cell responses to surface and architecture of tissue engineering scaffolds. In: Daniel E (ed) Regenerative medicine and tissue engineering—cells and biomaterials. InTech, Croatla. doi: 10.5772/21983
  11. Chinga-Carrasco G, Syverud K (2014) Pretreatment-dependent surface chemistry of wood nanocellulose for pH-sensitive hydrogels. J Biomater Appl 29:423–432. doi: 10.1177/0885328214531511 CrossRefGoogle Scholar
  12. Chinga-Carrasco G, Averianova N, Kondalenko O, Garaeva M, Petrov V, Leinsvang B, Karlsen T (2014) The effect of residual fibres on the micro-topography of cellulose nanopaper. Micron 56:80–84. doi: 10.1016/j.micron.2013.09.002 CrossRefGoogle Scholar
  13. Czaja WK, Young DJ, Kawecki M, Brown RM Jr (2007) The future prospects of microbial cellulose in biomedical applications. Biomacromolecules 8:1–12. doi: 10.1021/bm060620d CrossRefGoogle Scholar
  14. Eckardt NA (2008) Role of xyloglucan in primary cell walls. Plant Cell 20:1421–1422. doi: 10.1105/tpc.108.061382 CrossRefGoogle Scholar
  15. Eisenbarth E, Meyle J, Nachtigall W, Breme J (1996) Influence of the surface structure of titanium materials on the adhesion of fibroblasts. Biomaterials 17:1399–1403CrossRefGoogle Scholar
  16. Eronen P, Osterberg M, Heikkinen S, Tenkanen M, Laine J (2011a) Interactions of structurally different hemicelluloses with nanofibrillar cellulose. Carbohydr Polym 86:1281–1290. doi: 10.1016/j.carbpol.2011.06.031 CrossRefGoogle Scholar
  17. Eronen P, Österberg M, Heikkinen S, Tenkanen M, Laine J (2011b) Interactions of structurally different hemicelluloses with nanofibrillar cellulose. Carbohydr Polym 86:1281–1290. doi: 10.1016/j.carbpol.2011.06.031 CrossRefGoogle Scholar
  18. Fukuzumi H, Saito T, Iwata T, Kumamoto Y, Isogai A (2009) Transparent and high gas barrier films of cellulose nanofibers prepared by TEMPO-mediated oxidation. Biomacromolecules 10:162–165. doi: 10.1021/bm801065u CrossRefGoogle Scholar
  19. George JT, Howard G (1963) Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol 17:15. doi: 10.1083/jcb.17.2.299 Google Scholar
  20. Goldschmid O (1954) Determination of phenolic hydroxyl content of lignin preparations by ultraviolet spectrophotometry. Anal Chem 26:1421–1423CrossRefGoogle Scholar
  21. Holback H, Yeo Y, Park K (2011) Hydrogel swelling behavior and its biomedical applications. In: Rimmer S (ed) Biomedical hydrogels. Woodhead Publishing, UK, pp 3–24CrossRefGoogle Scholar
  22. Hua K, Carlsson DO, Ålander E, Lindström T, Strømme M, Mihranyan A, Ferraz N (2014) Translational study between structure and biological response of nanocellulose from wood and green algae. RSC Adv 4:2892–2903. doi: 10.1039/c3ra45553j CrossRefGoogle Scholar
  23. Itoh S, Nakamura S, Nakamura M, Shinomiya K, Yamashita K (2006) Enhanced bone ingrowth into hydroxyapatite with interconnected pores by Electrical Polarization. Biomaterials 27:5572–5579. doi: 10.1016/j.biomaterials.2006.07.007 CrossRefGoogle Scholar
  24. Janmey PA, Miller RT (2011) Mechanisms of mechanical signaling in development and disease. J Cell Sci 124:9–18. doi: 10.1242/jcs.071001 CrossRefGoogle Scholar
  25. Johansson P et al (2004) Crystal structures of a poplar xyloglucan endotransglycosylase reveal details of transglycosylation acceptor binding. Plant cell 16:874–886. doi: 10.1105/tpc.020065 CrossRefGoogle Scholar
  26. Kabel MA, van den Borne H, Vincken JP, Voragen AGJ, Schols HA (2007) Structural differences of xylans affect their interaction with cellulose. Carbohydr Polym 69:94–105CrossRefGoogle Scholar
  27. Karaaslan MA, Tshabalala MA, Yelle DJ, Buschle-Diller G (2011) Nanoreinforced biocompatible hydrogels from wood hemicelluloses and cellulose whiskers. Carbohydr Polym 86:192–201. doi: 10.1016/j.carbpol.2011.04.030 CrossRefGoogle Scholar
  28. Kilpeläinen P, Kitunen V, Pranovich A, Ilvesniemi H, Willfor S (2013) Pressurized Hot Water Flow-through Extraction of Birch Sawdust with Acetate pH Buffer. Bioresources 8:5202–5218CrossRefGoogle Scholar
  29. Lin S, Sangaj N, Razafiarison T, Zhang C, Varghese S (2011) Influence of physical properties of biomaterials on cellular behavior. Pharm Res 28:1422–1430. doi: 10.1007/s11095-011-0378-9 CrossRefGoogle Scholar
  30. Linder A, Bergman R, Bodin A, Gatenholm P (2003) Mechanism of assembly of xylan onto cellulose surfaces. Langmuir ACS J Surf Colloids 19:5072–5077CrossRefGoogle Scholar
  31. Liu J, Korpinen R, Mikkonen K, Willför S, Xu C (2014) Nanofibrillated cellulose originated from birch sawdust after sequential extractions: a promising polymeric material from waste to films. Cellulose 21:2587–2598. doi: 10.1007/s10570-014-0321-4 CrossRefGoogle Scholar
  32. Liu J, Willför S, Xu C (2015) A review of bioactive plant polysaccharides: biological activities, functionalization, and biomedical applications. Bioact Carbohydr Diet Fibre 5:31–61CrossRefGoogle Scholar
  33. Liu J et al (2016) Development of nanocellulose scaffolds with tunable structures to support 3D cell culture. Carbohydr Polym 148:259–271CrossRefGoogle Scholar
  34. Lopez-Sanchez P, Cersosimo J, Wang D, Flanagan B, Stokes JR, Gidley MJ (2015) Poroelastic mechanical effects of hemicelluloses on cellulosic hydrogels under compression. PLOS One 10:e0122132. doi: 10.1371/journal.pone.0122132 CrossRefGoogle Scholar
  35. Lucenius J, Parikka K, Österberg M (2014) Nanocomposite films based on cellulose nanofibrils and water-soluble polysaccharides. React Funct Polym 85:167–174. doi: 10.1016/j.reactfunctpolym.2014.08.001 CrossRefGoogle Scholar
  36. Malinen MM, Kanninen LK, Corlu A, Isoniemi HM, Lou Y-R, Yliperttula ML, Urtti AO (2014) Differentiation of liver progenitor cell line to functional organotypic cultures in 3D nanofibrillar cellulose and hyaluronan-gelatin hydrogels. Biomaterials 35:5110–5121. doi: 10.1016/j.biomaterials.2014.03.020 CrossRefGoogle Scholar
  37. Martinez-Ruvalcaba A (2008) Swelling characterization and drug delivery kinetics of polyacrylamide-co-itaconic acid/chitosan hydrogels eXPRESS. Polym Lett 3:25–32. doi: 10.3144/expresspolymlett.2009.5 CrossRefGoogle Scholar
  38. Mehling T, Smirnova I, Guenther U, Neubert RHH (2009) Polysaccharide-based aerogels as drug carriers. J Non-Cryst Solids 355:2472–2479. doi: 10.1016/j.jnoncrysol.2009.08.038 CrossRefGoogle Scholar
  39. Mertaniemi H et al (2016) Human stem cell decorated nanocellulose threads for biomedical applications. Biomaterials 82:208–220. doi: 10.1016/j.biomaterials.2015.12.020 CrossRefGoogle Scholar
  40. Moroni L, de Wijn JR, van Blitterswijk CA (2006) 3D fiber-deposited scaffolds for tissue engineering: influence of pores geometry and architecture on dynamic mechanical properties. Biomaterials 27:974–985. doi: 10.1016/j.biomaterials.2005.07.023 CrossRefGoogle Scholar
  41. Muiznieks LD, Keeley FW (2013) Molecular assembly and mechanical properties of the extracellular matrix: a fibrous protein perspective. Biochim Biophys Acta 1832:866–875. doi: 10.1016/j.bbadis.2012.11.022 CrossRefGoogle Scholar
  42. Okay O (2010) General properties of hydrogels. In: Gerlach G, Arndt K-F (eds) Hydrogel sensors and actuators, vol vol 6., Springer Series on Chemical Sensors and BiosensorsSpringer, Heidelberg, pp 1–14. doi: 10.1007/978-3-540-75645-3_1 CrossRefGoogle Scholar
  43. Park YB, Cosgrove DJ (2015) Xyloglucan and its interactions with other components of the growing cell wall. Plant Cell Physiol 56:180–194CrossRefGoogle Scholar
  44. Pereira MM et al (2013) Cytotoxicity and expression of genes involved in the cellular stress response and apoptosis in mammalian fibroblast exposed to cotton cellulose nanofibers. Nanotechnology 24Google Scholar
  45. Petersen N, Gatenholm P (2011) Bacterial cellulose-based materials and medical devices: current state and perspectives. Appl Microbiol Biotechnol 91:1277–1286. doi: 10.1007/s00253-011-3432-y CrossRefGoogle Scholar
  46. Plant AL, Bhadriraju K, Spurlin TA, Elliott JT (2009) Cell response to matrix mechanics: focus on collagen. Biochim Biophys Acta (BBA)—Mol Cell Res 1793:893–902. doi: 10.1016/j.bbamcr.2008.10.012 CrossRefGoogle Scholar
  47. Popa V (2011) Polysaccharides in medicinal and pharmaceutical applications. Smithers Rapra, ShrewsburyGoogle Scholar
  48. Portal O, Clark WA, Levinson DJ (2009) Microbial cellulose wound dressing in the treatment of nonhealing lower extremity ulcers. Wounds 21:1–3Google Scholar
  49. Powell LC, Khan S, Chinga-Carrasco G, Wright CJ, Hill KE, Thomas DW (2016) An investigation of Pseudomonas aeruginosa biofilm growth on novel nanocellulose fibre dressings. Carbohydr Polym 137:191–197. doi: 10.1016/j.carbpol.2015.10.024 CrossRefGoogle Scholar
  50. Prakobna K, Kisonen V, Xu C, Berglund L (2015) Strong reinforcing effects from galactoglucomannan hemicellulose on mechanical behavior of wet cellulose nanofiber gels. J Mater Sci 50:7413–7423. doi: 10.1007/s10853-015-9299-z CrossRefGoogle Scholar
  51. Richards RG (1996) The effect of surface roughness on fibroblast adhesion in vitro. Injury 27(Suppl 3):SC38–43Google Scholar
  52. Rimmer SD (2011) Biomedical hydrogels: biochemistry, manufacture and medical applications. Woodhead Pub, OxfordCrossRefGoogle Scholar
  53. Rosario P (2013) Advances in biomaterials science and biomedical applications. InTech. doi: 10.5772/56420
  54. Saddiq ZA, Barbenel JC, Grant MH (2009) The mechanical strength of collagen gels containing glycosaminoglycans and populated with fibroblasts. J Biomed Mater Res Part A 89A:697–706. doi: 10.1002/jbm.a.32007 CrossRefGoogle Scholar
  55. Saito T, Nishiyama Y, Putaux J-L, Vignon M, Isogai A (2006) Homogeneous suspensions of individualized microfibrils from TEMPO-catalyzed oxidation of native cellulose. Biomacromolecules 7:1687–1691. doi: 10.1021/bm060154s CrossRefGoogle Scholar
  56. Sehaqui H, Zhou Q, Berglund LA (2011) High-porosity aerogels of high specific surface area prepared from nanofibrillated cellulose (NFC). Compos Sci Technol 71:1593–1599. doi: 10.1016/j.compscitech.2011.07.003 CrossRefGoogle Scholar
  57. Simkovic I (2013) Unexplored possibilities of all-polysaccharide composites. Carbohydr Polym 95:697–715. doi: 10.1016/j.carbpol.2013.03.040 CrossRefGoogle Scholar
  58. Sorimachi K, Watanabe K, Yamazaki S, Yasumura Y (1992) Inhibition of fibroblast growth by polyanions; effects of dextran sulfate and lignin derivatives. Cell Biol Int Rep 16:63–71CrossRefGoogle Scholar
  59. Stevanic JS, Mikkonen KS, Xu CL, Tenkanen M, Berglund L, Salmen L (2014) Wood cell wall mimicking for composite films of spruce nanofibrillated cellulose with spruce galactoglucomannan and arabinoglucuronoxylan. J Mater Sci 49:5043–5055CrossRefGoogle Scholar
  60. Syverud K, Chinga-Carrasco G, Toledo J, Toledo PG (2011) A comparative study of Eucalyptus and Pinus radiata pulp fibres as raw materials for production of cellulose nanofibrils. Carbohydr Polym 84:1033–1038. doi: 10.1016/j.carbpol.2010.12.066 CrossRefGoogle Scholar
  61. Syverud K, Pettersen S, Draget K, Chinga-Carrasco G (2014) Controlling the elastic modulus of cellulose nanofibril hydrogels—scaffolds with potential in tissue engineering. Cellulose 1–9 doi: 10.1007/s10570-014-0470-5
  62. Syverud K, Pettersen S, Draget K, Chinga-Carrasco G (2015) Controlling the elastic modulus of cellulose nanofibril hydrogels—scaffolds with potential in tissue engineering. Cellulose 22:473–481. doi: 10.1007/s10570-014-0470-5 CrossRefGoogle Scholar
  63. Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47:1394–1400. doi: 10.1002/hep.22193 CrossRefGoogle Scholar
  64. Wells RG (2013) Tissue mechanics and fibrosis. Biochim Biophys Acta 1832:884–890. doi: 10.1016/j.bbadis.2013.02.007 CrossRefGoogle Scholar
  65. Willför S, Rehn P, Sundberg A, Sundberg K, Holmbom B (2003) Recovery of water-soluble acetylgalactoglucomannans from mechanical pulp of spruce. TAPPI J 2:27–32Google Scholar
  66. Xu C, Leppanen AS, Eklund P, Holmlund P, Sjoholm R, Sundberg K, Willfor S (2010) Acetylation and characterization of spruce (Picea abies) galactoglucomannans. Carbohydr Res 345:810–816. doi: 10.1016/j.carres.2010.01.007 CrossRefGoogle Scholar
  67. Xu C, Spadiut O, Araújo AC, Nakhai A, Brumer H (2012) Chemo-enzymatic assembly of clickable cellulose surfaces via multivalent polysaccharides. ChemSusChem 5:661–665. doi: 10.1002/cssc.201100522 CrossRefGoogle Scholar
  68. Yang T, Malkoch M, Hult A (2013) Sequential interpenetrating poly(ethylene glycol) hydrogels prepared by UV-initiated thiol–ene coupling chemistry. J Polym Sci, Part A Polym Chem 51:363–371. doi: 10.1002/pola.26393 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Jun Liu
    • 1
  • Gary Chinga-Carrasco
    • 2
  • Fang Cheng
    • 3
    • 4
  • Wenyang Xu
    • 1
  • Stefan Willför
    • 1
  • Kristin Syverud
    • 2
    • 5
    Email author
  • Chunlin Xu
    • 1
    Email author
  1. 1.Johan Gadolin Process Chemistry Centre, c/o Laboratory of Wood and Paper ChemistryÅbo Akademi UniversityÅbo/TurkuFinland
  2. 2.Paper and Fibre Research Institute (PFI)TrondheimNorway
  3. 3.Department of BiosciencesÅbo Akademi UniversityTurkuFinland
  4. 4.Turku Centre for BiotechnologyUniversity of Turku and Åbo Akademi UniversityTurkuFinland
  5. 5.Department of Chemical EngineeringNorwegian University of Science and Technology (NTNU)TrondheimNorway

Personalised recommendations