Abstract
Hyaluronan has great potential in medicine as a biomaterial. However, in its native form, hyaluronan is rapidly metabolized in vivo by free radicals and enzymes such as hyaluronidase, and it is highly soluble. Various methods have been adopted therefore, to modify the physicochemical properties of hyaluronan, while maintaining biocompatibility, and thereby widen its spectrum of therapeutic applications.
Hyaluronan has four reactive groups (acetamido, carboxyl, hydroxyl and the reducing end) available for crosslinking to itself or other polymers. Using a variety of crosslinking agents, researchers have developed a host of crosslinked hyaluronan derivatives with an increased in vivo residence time. This chemical modification has enabled the production of gels and films, which can be used in applications such as the prevention of post-surgical adhesions, wound healing and dermal augmentation.
We have found that if hyaluronan is crosslinked to itself, or to other polymers (either synthetic or biopolymer), in two stages, then a high degree of crosslinking is achieved, conferring improved biostability. In each of the two stages, the same crosslinking agent is used, but different functional groups are bound by altering the reaction conditions. The novel process can be tailored to yield water insoluble gels and films with a broad range of physical and chemical characteristics, and greater resistance to degradation by hyaluronidase and free radicals. These derivatives are currently undergoing biocompatibility testing, and should ultimately lead to a series of innovative second-generation medical products.
Similar content being viewed by others
References
K. Meyer and J. W. Palmer, J. Biol. Chem. 107 (1934) 629.
K. P. Vercruysse and G. D. Prestwich, Crit. Rev. Ther. Drug. Carrier Syst. 15 (1998) 513.
M. T. Longaker and N. Adzick, Clin. Mater. 8 (1991) 223.
D. B. Johns, T. C. Kiorpes, K. E. Rodgers and G. S. Dizerega et al., Fertility and Sterility 68 (1997) 137.
F. Duranti, G. Salti, B. Bovani, M. Calanda and M. L. Rosati, Derm. Surg. 24 (1998) 1314.
E. Bell, Tissue Eng. 1 (1995) 163.
A. Rastrelli, M. Beccaro, F. Biviano, G. Calderini and A. Pastorello, Clin. Implant Mater. 9 (1990) 199.
A. D. Campoccia, P. Doherty, M. Radice, P. Brun, G. Abatangelo and D. F. Williams, Biomaterials. 19 (1998) 2101.
E. A. Balazs and A. Leshchiner, US Patent, 4,582,865, 1986.
N. Yui, T. Okano and S. Yasuhisa, J. Control. Release. 22 (1992) 105.
T. C. Laurent, K. Hellsing and B. Gelotte, Acta. Chem. Scand. 18 (1964) 274.
K. Tomihata and Y. Ikada, J. Polym. Sci. Part A-Polym. Chem. 35 (1997) 3553.
P. Bulpitt and D. Aeschlimann, J. Biomed. Mater. Res. 47 (1999) 152.
K. Tomihata and Y. Ikada, ibid. 37 (1997) 243.
W. M. Rhee and R. A. Berg, US Patent 5,510,121, 1996.
A. N. De Belder and T. Malson, US Patent 4,886,787, 1989.
K. T. Dickerson, J. R. Glass, L.-S. Liu, J. W. Polarek, W. S. Craig, D. G. Mullen and S. Cheng, US Patent 5,677,276, October 1997.
X. Zhao, WO 00/46253, August 2000.
X. Zhao, C. Alexander and J. Fraser, WO 00/46254, August 2000.
T. Bitter and H. M. Muir, Anal. Biochem. 4 (1962) 330.
K. Tomihata, Y. Ikada, Biomaterials. 18 (1997) 189.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhao, X.B., Fraser, J.E., Alexander, C. et al. Synthesis and characterization of a novel double crosslinked hyaluronan hydrogel. Journal of Materials Science: Materials in Medicine 13, 11–16 (2002). https://doi.org/10.1023/A:1013618115163
Issue Date:
DOI: https://doi.org/10.1023/A:1013618115163