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Thermoresponsive hyperbranched copolymer with multi acrylate functionality for in situ cross-linkable hyaluronic acid composite semi-IPN hydrogel

  • Yixiao Dong
  • Waqar Hassan
  • Yu Zheng
  • Aram Omer Saeed
  • Hongliang Cao
  • Hongyun Tai
  • Abhay Pandit
  • Wenxin Wang
Article

Abstract

Thermoresponsive polymers have been widely used for in situ formed hydrogels in drug delivery and tissue engineering as they are easy to handle and their shape can easily conform to tissue defects. However, non-covalent bonding and mechanical weakness of these hydrogels limit their applications. In this study, a physically and chemically in situ cross-linkable hydrogel system was developed from a novel thermoresponsive hyperbranched PEG based copolymer with multi acrylate functionality, which was synthesized via an ‘one pot and one step’ in situ deactivation enhanced atom transfer radical co-polymerization of poly(ethylene glycol) diacrylate (PEGDA, Mn = 258 g mol−1), poly(ethylene glycol) methyl ether methacrylate (PEGMEMA, M= 475 g mol−1) and (2-methoxyethoxy) ethyl methacrylate (MEO2MA). This hyperbranched copolymer was tailored to have the lower critical solution temperature to form physical gelation around 37°C. Meanwhile, with high level of acrylate functionalities, a chemically cross-linked gel was formed from this copolymer using thiol functional cross-linker of pentaerythritol tetrakis (3-mercaptopropionate) (QT) via thiol-ene Michael addition reaction. Furthermore, a semi-interpenetrated polymer networks (semi-IPN) structure was developed by combining this polymer with hyaluronic acid (HA), leading to an in situ cross-linkable hydrogel with significantly increased porosity, enhanced swelling behavior and improved cell adhesion and viability both in 2D and 3D cell culture models.

Keywords

Hyaluronic Acid Atom Transfer Radical Polymerization Lower Critical Solution Temperature Interpenetrate Polymer Network Copolymer Solution 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Science Foundation Ireland (SFI), SFI Principal Investigator programme, Heath Research Board (HRB) of Ireland, DEBRA Ireland and DEBRA Austria, National University of Ireland, Galway are gratefully acknowledged for funding. YD thanks Mohammad Abu-Rub and Estelle Collin in NFB for the help on hydrogel characterization and 3D cell culture work.

Supplementary material

10856_2011_4496_MOESM1_ESM.docx (77 kb)
Supplementary material 1 (DOCX 76 kb)

References

  1. 1.
    Anseth KS, Metters AT, Bryant SJ, Martens PJ, Elisseeff JH, Bowman CN. In situ forming degradable networks and their application in tissue engineering and drug delivery. J Control Release. 2002;78(1–3):199–209.CrossRefGoogle Scholar
  2. 2.
    Balakrishnan B, Jayakrishnan A. Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds. Biomaterials. 2005;26(18):3941–51.CrossRefGoogle Scholar
  3. 3.
    Elisseeff J. Injectable cartilage tissue engineering. Expert Opin Biol Ther. 2004;4(12):1849–59.CrossRefGoogle Scholar
  4. 4.
    Mano JF. Stimuli-responsive polymeric systems for biomedical applications. Adv Eng Mater. 2008;10(6):515–27.CrossRefGoogle Scholar
  5. 5.
    Yu L, Ding JD. Injectable hydrogels as unique biomedical materials. Chem Soc Rev. 2008;37(8):1473–81.CrossRefGoogle Scholar
  6. 6.
    Friedrich T, Tieke B, Stadler FJ, Bailly C, Eckert T, Richtering W. Thermoresponsive copolymer hydrogels on the basis of N-isopropylacrylamide and a non-ionic surfactant monomer: swelling behavior, transparency and rheological properties. Macromolecules. 2010;43(23):9964–71.CrossRefGoogle Scholar
  7. 7.
    Galperin A, Long TJ, Ratner BD. Degradable, thermo-sensitive poly(N-isopropyl acrylamide)-based scaffolds with controlled porosity for tissue engineering applications. Biomacromolecules. 2010;11(10):2583–92.CrossRefGoogle Scholar
  8. 8.
    Hatefi A, Amsden B. Biodegradable injectable in situ forming drug delivery systems. J Control Release. 2002;80(1–3):9–28.CrossRefGoogle Scholar
  9. 9.
    Jeong B, Gutowska A. Lessons from nature: stimuli-responsive polymers and their biomedical applications. Trends Biotechnol. 2002;20(7):305–11.CrossRefGoogle Scholar
  10. 10.
    Wang WX, Liang H, Al Ghanami RC, Hamilton L, Fraylich M, Shakesheff KM, Saunders B, Alexander C. Biodegradable thermoresponsive microparticle dispersions for injectable cell delivery prepared using a single-step process. Adv Mater. 2009;21(18):1809.CrossRefGoogle Scholar
  11. 11.
    Kwon IK, Matsuda T. Photo-iniferter-based thermoresponsive block copolymers composed of poly(ethylene glycol) and poly(N-isopropylacrylamide) and chondrocyte immobilization. Biomaterials. 2006;27(7):986–95.CrossRefGoogle Scholar
  12. 12.
    Potta T, Chun C, Song SC. Dual cross-linking systems of functionally photo-cross-linkable and thermoresponsive polyphosphazene hydrogels for biomedical applications. Biomacromolecules. 2010;11(7):1741–53.CrossRefGoogle Scholar
  13. 13.
    Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49(8):1993–2007.CrossRefGoogle Scholar
  14. 14.
    Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliver Rev. 2001;53(3):321–39.CrossRefGoogle Scholar
  15. 15.
    Lin CC, Anseth KS. PEG hydrogels for the controlled release of biomolecules in regenerative medicine. Pharm Res. 2009;26(3):631–43.CrossRefGoogle Scholar
  16. 16.
    Zhang Niu GG, HB Song L, Cui XP, Cao H, Zheng YD, Zhu SQ, Yang Z, Yang H. Thiol/acrylate-modified PEO-PPO-PEO triblocks used as reactive and thermosensitive copolymers. Biomacromolecules. 2008;9(10):2621–8.CrossRefGoogle Scholar
  17. 17.
    Rydholm AE, Bowman CN, Anseth KS. Degradable thiol-acrylate photopolymers: polymerization and degradation behavior of an in situ forming biomaterial. Biomaterials. 2005;26(22):4495–506.CrossRefGoogle Scholar
  18. 18.
    Hou DD, Hao T, Ye L, Zhang AY, Wang CY, Feng ZG, 4. Preparation and characterization of injectable hydrogels made via Michael-type addition reaction of dithiothreitol with 3-Arm acryloyl end-capped PEG. Acta Polym Sin. 2008;1(4):388–93.CrossRefGoogle Scholar
  19. 19.
    Vernon B, Tirelli N, Bachi T, Haldimann D, Hubbell JA. Water-borne, in situ crosslinked biomaterials from phase-segregated precursors. J Biomed Mater Res A. 2003;64A(3):447–56.CrossRefGoogle Scholar
  20. 20.
    Cheng V, Lee BH, Pauken C, Vernon BL. Poly(N-isopropylacrylamide-co-poly(ethylene glycol))-acrylate simultaneously physically and chemically gelling polymer systems. J Appl Polym Sci. 2007;106(2):1201–7.CrossRefGoogle Scholar
  21. 21.
    Cellesi F, Tirelli N, Hubbell JA. Materials for cell encapsulation via a new tandem approach combining reverse thermal gelation and covalent crosslinking. Macromol Chem Phys. 2002;203(10–11):1466–72.CrossRefGoogle Scholar
  22. 22.
    Cellesi F, Tirelli N, Hubbell JA. Towards a fully-synthetic substitute of alginate: development of a new process using thermal gelation and chemical cross-linking. Biomaterials. 2004;25(21):5115–24.CrossRefGoogle Scholar
  23. 23.
    Lee BH, West B, McLemore R, Pauken C, Vernon BL. In situ injectable physically and chemically gelling NIPAAm-based copolymer system for embolization. Biomacromolecules. 2006;7(6):2059–64.CrossRefGoogle Scholar
  24. 24.
    Tai H, Wang W, Vermonden T, Heath F, Hennink WE, Alexander C, Shakesheff KM, Howdle SM. Thermoresponsive and photocrosslinkable PEGMEMA-PPGMA-EGDMA copolymers from a one-step ATRP synthesis. Biomacromolecules. 2009;10:822–8.CrossRefGoogle Scholar
  25. 25.
    Dong YX, Gunning P, Cao HL, Mathew A, Newland B, Saeed AO, Magnusson JP, Alexander C, Tai HY, Pandit A, Wang WX. Dual stimuli responsive PEG based hyperbranched polymers. Polym Chem. 2010;1(10):827–30.CrossRefGoogle Scholar
  26. 26.
    Hoyle CE, Bowman CN. Thiol-ene click chemistry. Angew Chem Int Edit. 2010;49(9):1540–73.CrossRefGoogle Scholar
  27. 27.
    Smart JD. An invitro assessment of some mucosa-adhesive dosage forms. Int J Pharm. 1991;73(1):69–74.CrossRefGoogle Scholar
  28. 28.
    Chen SC, Wu YC, Mi FL, Lin YH, Yu LC, Sung HWJ. A novel pH-sensitive hydrogel composed of N,O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery. J Control Release. 2004;96(2):285–300.CrossRefGoogle Scholar
  29. 29.
    Zhang J, Peppas NA. Synthesis and characterization of pH- and temperature-sensitive poly(methacrylic acid)/poly(N-isopropylacrylamide) interpenetrating polymeric networks. Macromolecules. 2000;33(1):102–7.CrossRefGoogle Scholar
  30. 30.
    Zhang XZ, Wu DQ, Chu CC. Synthesis, characterization and controlled drug release of thermosensitive IPN-PNIPAAm hydrogels. Biomaterials. 2004;25(17):3793–805.CrossRefGoogle Scholar
  31. 31.
    Chen WYJ, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen. 1999;7(2):79–89.CrossRefGoogle Scholar
  32. 32.
    Ghosh K, Ren XD, Shu XZ, Prestwich GD, Clark RAF. Fibronectin functional domains coupled to hyaluronan stimulate adult human dermal fibroblast responses critical for wound healing. Tissue Eng. 2006;12(3):601–13.CrossRefGoogle Scholar
  33. 33.
    Lo GH, LaValley M, McAlindon T, Felson DT. Intra-articular hyaluronic acid in treatment of knee osteoarthritis—a meta-analysis. J Am Med Assoc. 2003;290(23):3115–21.CrossRefGoogle Scholar
  34. 34.
    Wang CT, Lin J, Chang CJ, Lin YT, Hou SM. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee—a meta-analysis of randomized controlled trials. J Bone Joint Surg Am. 2004;86A(3):538–45.Google Scholar
  35. 35.
    Nesti LJ, Li WJ, Shanti RM, Jiang YJ, Jackson W, Freedman BA, Kuklo TR, Giuliani JR, Tuan RS. Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. Tissue Eng A. 2008;14(9):1527–37.CrossRefGoogle Scholar
  36. 36.
    Nettles DL, Vail TP, Morgan MT, Grinstaff MW, Setton LA. Photocrosslinkable hyaluronan as a scaffold for articular cartilage repair. Ann Biomed Eng. 2004;32(3):391–7.CrossRefGoogle Scholar
  37. 37.
    Yamane S, Iwasaki N, Majima T, Funakoshi T, Masuko T, Harada K, Minami A, Monde K, Nishimura S. Feasibility of chitosan-based hyaluronic acid hybrid biomaterial for a novel scaffold in cartilage tissue engineering. Biomaterials. 2005;26(6):611–9.CrossRefGoogle Scholar
  38. 38.
    Fang JY, Chen JP, Leu YL, Hu HW. Temperature-sensitive hydrogels composed of chitosan and hyaluronic acid as injectable carriers for drug delivery. Eur J Pharm Biopharm. 2008;68(3):626–36.CrossRefGoogle Scholar
  39. 39.
    Kurisawa M, Chung JE, Yang YY, Gao SJ, Uyama H. Injectable biodegradable hydrogels composed of hyaluronic acid-tyramine conjugates for drug delivery and tissue engineering. Chem Commun. 2005;14(34):4312–4.CrossRefGoogle Scholar
  40. 40.
    Luo Y, Kirker KR, Prestwich GD. Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery. J Control Release. 2000;69(1):169–84.CrossRefGoogle Scholar
  41. 41.
    Kutty JK, Cho E, Lee JS, Vyavahare NR, Webb K. The effect of hyaluronic acid incorporation on fibroblast spreading and proliferation within PEG-diacrylate based semi-interpenetrating networks. Biomaterials. 2007;28(33):4928–38.CrossRefGoogle Scholar
  42. 42.
    Cesaretti M, Luppi E, Maccari F, Volpi N. A 96-well assay for uronic acid carbazole reaction. Carbohydr Polym. 2003;54(1):59–61.CrossRefGoogle Scholar
  43. 43.
    Wang WX, Zheng Y, Roberts E, Duxbury CJ, Ding LF, Irvine DJ, Howdle SM. Controlling chain growth: a new strategy to hyperbranched materials. Macromolecule. 2007;40:7184.CrossRefGoogle Scholar
  44. 44.
    Lutz JF, Weichenhan K, Akdemir O, Hoth A. About the phase transitions in aqueous solutions of thermoresponsive copolymers and hydrogels based on 2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene glycol) methacrylate. Macromolecules. 2007;40(7):2503–8.CrossRefGoogle Scholar
  45. 45.
    Hedberg EL, Tang A, Crowther RS, Carney DH, Mikos AG. Controlled release of an osteogenic peptide from injectable biodegradable polymeric composites. J Control Release. 2002;84(3):137–50.CrossRefGoogle Scholar
  46. 46.
    Lih E, Joung YK, Bae JW, Park KD. An in situ gel-forming heparin-conjugated PLGA-PEG-PLGA copolymer. J Bioact Compat Polym. 2008;23(5):444–57.CrossRefGoogle Scholar
  47. 47.
    Nuttelman CR, Tripodi MC, Anseth KS. In vitro osteogenic differentiation of human mesenchymal stem cells photoencapsulated in PEG hydrogels. J Biomed Mater Res A. 2004;68A(4):773–82.CrossRefGoogle Scholar
  48. 48.
    Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003;24(24):4337–51.CrossRefGoogle Scholar
  49. 49.
    Wang CM, Varshney RR, Wang DA. Therapeutic cell delivery and fate control in hydrogels and hydrogel hybrids. Adv Drug Deliver Rev. 2010;62(7–8):699–710.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yixiao Dong
    • 1
  • Waqar Hassan
    • 1
  • Yu Zheng
    • 1
  • Aram Omer Saeed
    • 1
  • Hongliang Cao
    • 1
  • Hongyun Tai
    • 2
  • Abhay Pandit
    • 1
  • Wenxin Wang
    • 1
  1. 1.Network of Excellence for Functional BiomaterialsNational University of IrelandGalwayIreland
  2. 2.School of ChemistryBangor UniversityBangorUK

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