Review

Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids   Riccardo A.A. Muzzarelli

A review article

Carbohydrate Polymers, 77, 1-9. 2009

Elsevier, Amsterdam.

Genipin, a crystalline and well defined chemical compound, is extracted from gardenia fruits according to a modern microbiological process. As a water-soluble bi-functional crosslinking reagent, it reacts promptly with chitosan (and with proteins or amines in general) thus producing blue-coloured fluorescent hydrogels. The reaction mechanism between chitosan and genipin is well understood for a variety of experimental conditions. The resulting crosslinked complexes are not cytotoxic for the animal and human cells so far examined. The safety and the beneficial actions of genipin emerge from a number of research projects in the areas of the therapies of diabetes, periodontitis, cataract, hepatic dysfunction, as well as in wound repair and nerve regeneration. Food sciences, forensic chemistry and cytology have also provided evidence of the safety of its use. The most important applications of genipin in conjunction with chitosan are the preparation of elastic and resistant gels such as the cartilage substitutes, the manufacture of drug carriers for controlled release, the encapsulation of biological products and living cells, and the medication of wounds in animals and humans. Genipin might replace glutaraldehyde with the advantages of stability and biocompatibility of the crosslinked products whose quality assessment and manipulation would be easier.

Jayakumar R. and Prabaharan A. (Eds.)

Current research and development on chitin and chitosan in biomaterial science.

Vol. 2, p. 1-20: Research Signpost, Trivandrum, India, 2009.

Genipin cross-linking of chitosans

for drug delivery applications

A chapter by

Youling Yuan, Joel D. Bumgardner, Betsy M. Chesnutt,

Warren O. Haggard and Riccardo A.A. Muzzarelli

Biomedical Engineering Department, Herff College of Engineering, University of Memphis, Joint University of Memphis-University of Tennessee Health Science Center Program in Biomedical Engineering, Memphis, TN, USA

ABSTRACT

Chitosan is widely studied in drug delivery systems since it can be prepared in gels, films, tablets, capsules, microspheres/microparticles, nano-particles, and fibers by different methods for a wide range of drugs and drug delivery applications. Cross-linking reagents, such as glutaraldehyde, tripolyphosphate, ethylene glycol, diglycidyl ether and diisocyanate have been used to increase drug release time frames from chitosan materials. However, these synthetic cross-linking reagents are highly or relatively highly cytotoxic which may impair biocompatibility of chitosan delivery systems. Genipin, a natural molecule, has shown promise as an alternative biocompatible cross-linker due to the very low toxicity of genipin and genipin cross-linked materials in vitro and in vivo. The scope of this chapter is to provide an overview of recent studies on the cross-linking reactions of genipin with chitosan and the influence of cross-linking on properties and release of drugs/ proteins from chitosan microspheres, gels and films.

In general cross-linking reactions occur via nucleophilic attach of chitosan amines on the dihydropyran ring of the genipin molecule. At low to neutral pH’s short cross-link bridges are obtained, while at basic pH’s long cross-link bridges occur. Cross-linking also decreases gelation and increases stability of chitosan gels, films and beads. Together, these effects typically result in extended delivery times. Additionally, encapsulation of cells and drugs in cross-linked chitosans has been used in minimally invasive applications. These results strongly support the continued development and use of genipin cross-linked chitosans for clinical drug delivery applications.