Ocular biocompatibility of carbodiimide cross-linked hyaluronic acid hydrogels for cell sheet delivery carriers

Jui Yang Lai*, David Hui Kang Ma, Hsiao Yun Cheng, Chi Chin Sun, Shu Jung Huang, Ya Ting Li, Ging Ho Hsiue

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

90 Scopus citations


Due to its innocuous nature, hyaluronic acid (HA) is one of the most commonly used biopolymers for ophthalmic applications. We recently developed a cell sheet delivery system using carbodiimide cross-linked HA carriers. Chemical cross-linking provides an improvement in stability of polymer gels, but probably causes toxic side-effects. The aim of this study was to investigate the ocular biocompatibility of HA hydrogels cross-linked by 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC). HA discs without cross-linking and glutaraldehyde (GTA) cross-linked HA samples were used for comparison. The disc implants were inserted in the anterior chamber of rabbit eyes for 24 weeks and characterized by slit-lamp biomicroscopy, histology and scanning electron microscopy. The ophthalmic parameters obtained from biomicroscopic examinations were also scored to provide a quantitative grading system. Results of this study showed that the HA discs cross-linked with EDC had better ocular biocompatibility than those with GTA. The continued residence of GTA cross-linked HA implants in the intraocular cavity elicited severe tissue responses and significant foreign body reactions, whereas no adverse inflammatory reaction was observed after contact with non-cross-linked HA or EDC cross-linked HA samples. It is concluded that the cross-linking agent type gives influence on ocular biocompatibility of cell carriers and the EDC-HA hydrogel is an ideal candidate for use as an implantable material in cell sheet delivery applications.

Original languageEnglish
Pages (from-to)359-376
Number of pages18
JournalJournal of Biomaterials Science, Polymer Edition
Issue number3
StatePublished - 01 02 2010


  • Cell sheet delivery
  • Chemical cross-linking
  • Hyaluronic acid
  • Hydrogel carrier
  • Ocular biocompatibility


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