Topical Administration of Freeze-Dried Sheets of Hyaluronic Acid Promotes the Healing of Oral Mucositis in a Hamster Model

Treatment of tumors in the head and neck region using anticancer agents or radiotherapy often causes oral mucositis, which is associated with severe mucosal pain. Hyaluronic acid (HA) is a moisturizing agent used clinically to treat oral mucositis; however, HA does not remain long-term in the mucositis region due to its liquid nature. We recently developed the original sheet form HA using a freeze-drying method. In this study, we evaluated the effect of topical application of the newly developed HA sheets on oral mucositis healing using an animal model. Experimental oral mucositis was induced in 6-week-old male Syrian hamsters by applying filter paper soaked with acetic acid to the cheek pouches. After determining the appropriate conditions for obtaining uniform mucositis region useful for evaluating the healing process, the effect of HA sheets on oral mucositis healing were evaluated macroscopically and histopathologically comparing three groups: an HA group, in which HA sheets were applied to the mucositis region from the second day after mucositis induction; a carboxymethylcellulose (CMC) control group treated with CMC sheets; and a control group in which no sheets were applied. Compared to the control group, the HA group exhibited significantly smaller mucositis region on Days 2-4. Histopathology analysis on Day 2 showed mild inflammatory cell infiltration, reduced edematous changes, partial regeneration of the oral mucosal epithelium, and parallel thick bundles of collagen fibers in the superficial layer in the HA group compared with the Control and CMC groups. In conclusion, a hamster oral mucositis model was established that allows for convenient evaluation of the healing process. Daily topical application of freeze-dried sheets of HA accelerated the healing of oral mucositis in this hamster model. These results suggest that HA sheets could be an effective material in the treatment of oral mucositis in cancer patients.