Macromolecular Research

, Volume 14, Issue 1, pp 87–93 | Cite as

Preparation of thermo-responsive and injectable hydrogels based on hyaluronic acid and poly(N-isopropylacrylamide) and their drug release behaviors

  • Dong In Ha
  • Sang Bong Lee
  • Moo Sang Chong
  • Young Moo Lee
  • So Yeon Kim
  • Young Hoon Park


Copolymers composed of hyaluronic acid (HA) and poly(N-isopropylacrylamide) (PNIPAAm) were prepared to create temperature-sensitive injectable gels for use in controlled drug delivery applications. Semi-telechelic PNIPAAm, with amino groups at the end of each main chain, was synthesized by radical polymerization using 2-aminoethanethiol hydrochloride (AESH) as the chain transfer agent, and was then grafted onto the carboxyl groups of HA using carbodiimide chemistry. The result of the thermo-optical analysis revealed that the phase transition of the PNIPAAm-grafted HA solution occurred at around 30∼33°C. As the graft yield of PNIPAAm onto the HA backbone increased, the HA-g-PNIPAAm copolymer solution exhibited sharper phase transition. The short chain PNIPAAm-grafted HA (M w =6,100) showed a narrower temperature range for optical turbidity changes than the long chain PNIPAAm-grafted HA (M w = 13,100). PNIPAAm-grafted HA exhibited an increase in viscosity above 35°C, thus allowing the gels to maintain their shape for 24 h afterin vivo administration. From thein vitro riboflavin release study, the HA-g-PNIPAAm gel showed a more sustained release behavior when the grafting yield of PNIPAAm onto the HA backbone was increased. In addition, BSA released from the PNIPAAm-g-HA gels showed a maximum concentration in the blood 12 h after being injected into the dorsal surface of a rabbit, followed by a sustained release profile after 60 h.


hyaluronic acid poly(N-isopropylacrylamide) injectable gel drug delivery 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. (1).
    A. S. Hoffman,Adv. Drug Deliver. Rev.,43, 3 (2002).CrossRefGoogle Scholar
  2. (2).
    J. A. Hubbell,Curr. Opin. Solid St. M.,3, 246 (1998).CrossRefGoogle Scholar
  3. (3).
    L. G. Griffith,Acta Materialia,48, 263 (2000).CrossRefGoogle Scholar
  4. (4).
    A. Gutowska, B. Jeong, and M. Jasionowski,The Anatomical Record,263, 342 (2001).CrossRefGoogle Scholar
  5. (5).
    S. Kim and K. E. Healy,Biomacromolecules,4, 1214 (2003).CrossRefGoogle Scholar
  6. (6).
    T. A. Holland, Y. Tabata, and A. G. Mikos,J. Control. Release,91, 299 (2003).CrossRefGoogle Scholar
  7. (7).
    S. R. Van Tomme, M. J. van Steenbergen, S. C. De Smedt, C. F. van Nostrum, and W. E. Hennink,Biomaterials,26, 2129 (2005).CrossRefGoogle Scholar
  8. (8).
    X. Z. Shu, Y. Liu, F. S. Palumbo, Y. Luo, and G. D. Prestwich,Biomaterials,25, 1339 (2004).CrossRefGoogle Scholar
  9. (9).
    S. Cai, Y. Liu, X. Z. Shu, and G. D. Prestwich,Biomaterials,26, 6054 (2005).CrossRefGoogle Scholar
  10. (10).
    K. Y. Cho, T. W. Chung, B. C. Kim, M. K. Kim, J. H. Lee, W. R. Wee, and C. S. Cho,J. of Pharmaceutics,260, 83 (2003).CrossRefGoogle Scholar
  11. (11).
    A. Chenite, C. Chaput, D. Wang, C. Combes, M. D. Buschmann, C. D. Hoemann, J. C. Leroux, B. L. Atkinson, F. Binette, and A. Selmani,Biomaterials,21, 2155 (2000).CrossRefGoogle Scholar
  12. (12).
    J. L. West and J. A. Hubbell,Macromolecules,32, 241 (1999).CrossRefGoogle Scholar
  13. (13).
    B. K. Mann, A. S. Gobin, A. T. Tsai, R. H. Schmedlen, and J. L. West,Biomaterials,22, 3045 (2001).CrossRefGoogle Scholar
  14. (14).
    Y. D. Park, N. Tirelli, and J. A. Hubbell,Biomaterials,24, 893 (2003).CrossRefGoogle Scholar
  15. (15).
    H. G. Schild,Prog. Polym. Sci.,17, 163 (1992).CrossRefGoogle Scholar
  16. (16).
    R. Yoshida, K. Sakai, T. Okano, and Y. Sakurai,J. Biomat. Sci.-Polym. E,6, 585 (1994).CrossRefGoogle Scholar
  17. (17).
    T. Inoue, G. Chen, K. Nakamae, and A. S. Hoffman,Polym. Gels Netw.,5, 561 (1997).CrossRefGoogle Scholar
  18. (18).
    M. Ebara, T. Aoyagi, K. Sakai, and T. Okano,Macromolecules,33, 8312 (2000).CrossRefGoogle Scholar
  19. (19).
    J. Zhang and N. A. Peppas,Macromolecules,33, 102 (2000).CrossRefGoogle Scholar
  20. (20).
    G. Chen and A. S. Hoffman,Bioconjugat. Chem.,4, 509 (1993).CrossRefGoogle Scholar
  21. (21).
    Y. Kaneko, K. Sakai, A. Kikuchi, R. Yoshida, Y. Sakurai, and T. Okano,Macromolecules,28, 7717 (1995).CrossRefGoogle Scholar
  22. (22).
    Y. Kanejo, S. Nakamura, K. Sakai, A. Kikuchi, T. Aoyagi, and T. Okano.Polym. Gels Netw.,6, 333 (1988).CrossRefGoogle Scholar
  23. (23).
    S. Ohya, H. Sonoda, Y. Nakayama, and T. Matsuda,Biomaterials,26, 655 (2005).CrossRefGoogle Scholar
  24. (24).
    H. K. Ju, S. Y. Kim, S. J. Kim, and Y. M. Lee,J. Appl. Polym. Sci.,83, 1128 (2002).CrossRefGoogle Scholar
  25. (25).
    H. K. Ju, S. Y. Kim, and Y. M. Lee,Polymer,42, 6851 (2001).CrossRefGoogle Scholar
  26. (26).
    J. H. Kim, S. B. Lee, S. J. Kim, and Y. M. Lee,Polymer,43, 7549 (2002).CrossRefGoogle Scholar
  27. (27).
    M. R. Kim and T. G. Park,J. Control. Release,80, 69 (2002).CrossRefGoogle Scholar
  28. (28).
    K. Pietrucha,Int. J. Biol. Macromol.,36, 299 (2005).CrossRefGoogle Scholar
  29. (29).
    S.Y. Kim, S. M. Cho, Y. M. Lee, and S. J. Kim,J. Appl. Polym. Sci.,78, 1381 (2000).CrossRefGoogle Scholar
  30. (30).
    Y. C. Bae, S. M. Lander, D. S. Soane, and M. Prauzsnitz,Macromolecules,24, 4403 (1991).CrossRefGoogle Scholar
  31. (31).
    H. Liu, Y. Yin, K. Yao, D. Ma, L. Cui, and Y. Cao,Biomaterials,25, 3523 (2004).CrossRefGoogle Scholar

Copyright information

© The Polymer Society of Korea and Springer 2006

Authors and Affiliations

  • Dong In Ha
    • 1
  • Sang Bong Lee
    • 1
  • Moo Sang Chong
    • 1
  • Young Moo Lee
    • 1
  • So Yeon Kim
    • 2
  • Young Hoon Park
    • 3
  1. 1.School of Chemical Engineering, College of EngineeringHanyang UniversitySeoulKorea
  2. 2.Nanomaterials Application DivisionKorea Institute of Ceramic Engineering and TechnologySeoulKorea
  3. 3.Department of Polymer EngineeringSunchon National UniversityJeonnamKorea

Personalised recommendations